U.S. patent application number 10/657815 was filed with the patent office on 2004-08-05 for arylglycine derivatives and their use as glycine transport inhibitors.
This patent application is currently assigned to NPS Allelix Corporation. Invention is credited to Arora, Jalaj, Begleiter, Leah, Da Silva-Turcot, Kathleen, Edwards, Louise, Isaac, Methvin, Maddaford, Shawn, O'Brien, Anne, Slassi, Abdelmalik, Stefanac, Tomislav, Xin, Tao.
Application Number | 20040152741 10/657815 |
Document ID | / |
Family ID | 31978756 |
Filed Date | 2004-08-05 |
United States Patent
Application |
20040152741 |
Kind Code |
A1 |
Isaac, Methvin ; et
al. |
August 5, 2004 |
Arylglycine derivatives and their use as glycine transport
inhibitors
Abstract
The present invention relates to compounds of Formula 1, 1 and
salts solvates and hydrates thereof. The invention further relates
to pharmaceutical compositions containing said compounds and
methods of treating neurological, neuropsychiatric, and
gastrointestinal disorders using said compounds.
Inventors: |
Isaac, Methvin; (Etobicoke,
CA) ; Xin, Tao; (Woodbridge, CA) ; Edwards,
Louise; (Mississauga, CA) ; Begleiter, Leah;
(Toronto, CA) ; Stefanac, Tomislav; (Burlington,
CA) ; O'Brien, Anne; (Toronto, CA) ; Da
Silva-Turcot, Kathleen; (Toronto, CA) ; Arora,
Jalaj; (Milton, CA) ; Maddaford, Shawn;
(Mississauga, CA) ; Slassi, Abdelmalik;
(Mississauga, CA) |
Correspondence
Address: |
JOHN W. RYAN
C/O DECHERT LLP
PRINCETON PIKE CORPORATION CENTER
P.O. BOX 5218
PRINCETON
NJ
08543-5218
US
|
Assignee: |
NPS Allelix Corporation
Mississauga
CA
|
Family ID: |
31978756 |
Appl. No.: |
10/657815 |
Filed: |
September 8, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60409421 |
Sep 9, 2002 |
|
|
|
Current U.S.
Class: |
514/352 ;
514/426; 514/586; 514/597; 546/305; 548/557; 564/21; 564/48 |
Current CPC
Class: |
C07C 2602/10 20170501;
C07C 335/16 20130101; A61P 25/28 20180101; C07C 279/28 20130101;
C07D 215/40 20130101; C07D 295/26 20130101; C07D 215/38 20130101;
A61P 25/18 20180101; C07C 2601/14 20170501; C07C 275/40 20130101;
C07D 213/75 20130101; C07C 335/18 20130101; C07C 2602/08 20170501;
C07D 333/24 20130101 |
Class at
Publication: |
514/352 ;
514/426; 514/586; 514/597; 546/305; 548/557; 564/021; 564/048 |
International
Class: |
C07D 213/75; A61K
031/44; A61K 031/40; C07D 207/34; A61K 031/17 |
Claims
We claim:
1. A compound of Formula 1: 184wherein: R.sub.1 is selected from
cycloalkyl, heterocycloalkyl, aryl and heteroaryl wherein R.sub.1
is optionally substituted with one or more substituents R.sub.a,
wherein R.sub.a is independently selected from the group consisting
of alkyl, halo, haloalkyl, nitro, alkenyl, alkynyl, alkoxy,
-(R.sub.7).sub.nNR.sub.- 8R.sub.9 (wherein R.sub.7 is selected from
alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a 5 or 6-member
heterocyclic ring, and n is selected from 0 and 1), and the
substituent R.sub.a is optionally further substituted with one or
more substituents selected from the group consisting of alkyl,
alkoxy, halo, cyano, alkanoyl, haloalkyl, thioalkyl and nitro,
--(R.sub.7).sub.nNR.sub.- 8R.sub.9, wherein R.sub.7, R.sub.8,
R.sub.9, and n are as defined above. R.sub.2 and R.sub.3 are: a)
independently selected from the group consisting of H, alkyl,
haloalkyl, aralkyl optionally substituted aryl, optionally
substituted heteroaryl and optionally substituted, saturated or
unsaturated, 5-or 6-membered, homocyclic or heterocyclic rings
wherein the optional substituent may be selected from the group
consisting of H, alkyl, alkoxy, and halo; or b) join together to
form a 3, 4, 5, 6 or 7 member spirocyclic ring; X is slelected from
O, S, NH and NCN; Ar.sub.1 is phenyl and is optionally substituted
with one or more substituents R.sub.b, wherein the substituent(s)
R.sub.b are independently selected from the group consisting of
alkyl, alkoxy, nitro halo, haloalkoxy,
--(R.sub.7).sub.nNR.sub.8R.sub.9, --S(O).sub.2NR.sub.10R.sub.11 and
--O--(CH.sub.2).sub.mNR.sub.10R.sub.11 (wherein R.sub.7 is selected
from alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a 5 or 6-member
heterocyclic ring, and n is selected from 0, 1, 2, 3, 4 and 5 and
R.sub.10 and R.sub.11 are independently selected from H, or alkyl,
or R.sub.10 and R.sub.11 can join together such that
NR.sub.10R.sub.11to form a 5 or 6-member heterocyclic ring and m is
selected from 1, 2, 3, 4 and 5) and; the substituent R.sub.b is
optionally further substituted with one or more substituents
selected from the group consisting of alkyl, alkoxy, halo, cyano,
alkanoyl, haloalkyl, thioalkyl, nitro, --(R.sub.7).sub.nNR.sub.8R.-
sub.9 wherein R.sub.7, R.sub.8, R.sub.9 and n are as described
above, with the proviso that Ar.sub.1 does not have a substituent
at the 2-position selected from the following groups, nitro,
haloalkyl, cyano, --C(O)R.sub.12 --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.13, --S(O)R.sub.12, --S(O).sub.2R.sub.12, and
--S(O).sub.2NR.sub.12R.sub.13 (wherein R.sub.12 and R.sub.13 are
independently selected from H and alkyl), and, the second proviso
that Ar.sub.1 does not have an alkanoyl substituent at the 4
position, and a salt solvate or hydrate thereof.
2. A compound of claim 1 wherein Ar.sub.1 is substituted with one
or more substituents, R.sub.a, wherein the substituent(s) R.sub.a
are selected from the group consisting of alkyl, alkoxy, nitro,
acetyl, halo, haloalkyl, --S(O).sub.2NR.sub.10R.sub.11,
--O-(CH.sub.2).sub.nNR.sub.10R.- sub.11, wherein R.sub.10 and
R.sub.11 are independently selected from H, or alkyl, or R.sub.10
and R.sub.11 can join together such that NR.sub.10R.sub.11 form a 5
or 6 member heterocyclic ring.
3. A compound of claim 2 wherein there are two substituents
R.sub.6, independently selected from the group consisting of nitro,
methoxy, and ethoxy.
4. A compound of claim 3 wherein the two substituents R.sub.6 are a
nitro substituent at the 5-position and a methoxy substituent at
the 2-position.
5. A compound as defined in claim 1 wherein R.sub.1 is optionally
substituted and is selected from the group consisting of phenyl,
naphthyl, tetrahydro-naphthyl, indanyl, quinolinyl and pyridyl.
6. A compound of claim 5 wherein R.sub.1 is indanyl.
7. A compound of claim 5 wherein R.sub.1 is optionally substituted
pyridyl wherein the substituent(s) R.sub.a are selected from the
group consisting of alkyl, and haloalkyl.
8. A compound of claim 5 wherein R.sub.1 is optionally substituted
phenyl wherein the substituent(s) R.sub.a are selected from the
group consisting of alkyl, halo, haloalkyl, nitro, vinyl, alkoxy,
--(R.sub.7).sub.nNR.sub.- 8R.sub.9 wherein R.sub.7 is selected from
alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a heterocyclic
ring, and n is selected from 0 and 1.
9. A compound of claim 8 wherein R.sub.1 is selected from mono or
di-substituted phenyl with the substituents selected independently
from the group consisting of alkyl, halo and haloalkyl.
10. A compound as defined in claim 1 wherein R.sub.2 and R.sub.3
are independently selected from, H, alkyl, aralkyl, optionally
substituted aryl, optionally substituted heteroaryl and optionally
substituted saturated or unsaturated 5 or 6-membered homocyclic, or
heterocyclic rings.
11. A compound as defined in claim 10 wherein R.sub.2 and R.sub.3
are selected independently from H, phenyl, 3-thiophene, sec-butyl,
3,4-difluorophenyl, cyclohexyl, 3-trifuoromethylphenyl, t-butyl,
isopropyl, methyl, benzyl, trifuoromethyl.
12. A compound as defined in claim 10 wherein R.sub.2 and R.sub.3
together form a 3, 5 or 6 member spirocycle.
13. A compound of claim 1 selected from the group consisting of:
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(2-indanyl)-2-(3-thienyl)
acetamide E42.2;
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimet-
hylphenyl)-2-phenyl acetamide E32.2;
2-[3-(2-methoxy-5-nitro-phenyl)-ureid-
o]-N-(3,4-dimethylphenyl)-2-phenyl acetamide E32.5;
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylphenyl)-2--
phenyl acetamide E33.1*;
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(2-inda-
nyl)-2-(3-thienyl) acetamide E42.1; (R)-2-[3-(2-nitro
-5-methoxy-phenyl)-ureido]-N-(2-indanyl)-2-phenyl acetamide E29.1
*;
(R)-2-[3-(2-nitro-5-methoxy-phenyl)-ureido]-N-(4-chlorophenyl)-2-phenyl
acetamide E4.1; and
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3-trif-
luromethylphenyl)-2-phenyl acetamide E31.2.
14. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 and a pharmaceutically
acceptable carrier.
15. A method for treating a patient having a medical condition for
which a glycine transport inhibitor is indicated, comprising the
step of administering to a patient a pharmaceutical composition as
described in claim 14.
16. A method according to claim 15 wherein the medical condition is
schizophrenia, cognitive dysfunction, or Alzheimer's disease.
Description
[0001] This application claims priority to U.S. Provisional
Application No. 60/409,421 filed Sep. 9, 2002.
[0002] The present invention relates to a class of compounds, to
pharmaceutical compositions containing them and to methods of
treating neurological and neuropsychiatric and gastrointestinal
disorders using such compounds.
BACKGROUND OF THE INVENTION
[0003] Synaptic transmission is a complex form of intercellular
communication that involves a considerable array of specialized
structures in both the pre- and post-synaptic terminal and
surrounding glial cells (Kanner and Schuldiner, CRC Critical
Reviews in Biochemistry, 22, 1987:1032). Transporters sequester
neurotransmitters from the synapse, thereby regulating the
concentration of neurotransmitters in the synapse, and their
duration therein, which together influence the magnitude of
synaptic transmission. Further, by preventing the spread of
neurotransmitter to neighbouring synapses, transporters maintain
the fidelity of synaptic transmission. Lastly, by sequestering
released neurotransmitter into the presynaptic terminal,
transporters allow for neurotransmitter re-utilization.
[0004] Neurotransmitter transport is dependent upon extracellular
sodium and the voltage difference across the membrane. Under
conditions of intense neuronal firing, for example, during a
seizure, transporters can function in reverse, releasing
neurotransmitter in a calcium-independent non-exocytotic manner
(Attwell et al., Neuron, 11, 1993:401-407). Pharmacologic
modulation of neurotransmitter transporters thus provides a means
for modifying synaptic activity, which provides useful therapy for
the treatment of neurological and psychiatric disturbances.
[0005] The amino acid glycine is a major neurotransmitter in the
mammalian central nervous system, functioning at both inhibitory
and excitatory synapses. By nervous system, both the central and
peripheral portions of the nervous system are intended. These
distinct functions of glycine are mediated by two different types
of receptor, the glycine receptor and the NMDA receptor, each of
which is associated with a different class of glycine transporter.
The inhibitory actions of glycine are mediated by glycine receptors
that are sensitive to the convulsant alkaloid strychnine, and are
thus referred to as "strychnine-sensitive", Such receptors contain
an intrinsic chloride channel that is opened upon binding of
glycine to the receptor; by increasing chloride conductance, the
threshold for firing of an action potential is increased.
Strychnine-sensitive glycine receptors are found predominantly in
the spinal cord and brainstem, and pharmacological agents that
enhance the activation of such receptors will thus increase
inhibitory neurotransmission in these regions.
[0006] Glycine also functions in excitatory transmission by
modulating the actions of glutamate, the major excitatory
neurotransmitter in the central nervous system (Johnson and Ascher,
Nature, 325, 1987:529-531; Fletcher et al., Glycine Transmission,
Otterson and Storm-Mathisen, eds., 1990:193-219). Specifically,
glycine is thought to be an obligatory co-agonist at the class of
glutamate receptor termed N-methyl-D-aspartate (NMDA) receptor.
Activation of NMDA receptors increases sodium and calcium
conductance, which depolarizes the neuron, thereby increasing the
likelihood that it will fire an action potential.
[0007] NMDA receptors in the hippocampal region of the brain play
an important role in a model of synaptic plasticity known as
long-term potentiation (LTP), which is integral in certain types of
learning and memory (Hebb, D. O (1949) The Organization of
Behavior, Wiley, N.Y.; Bliss and Collingridge (1993) Nature 361:
31-39; Morris et al. (1986) Nature 319: 774-776). Enhanced
expression of selected NMDA receptor sub-units in transgenic mice
results in increased NMDA-receptor-mediated currents, enhanced LTP,
and better performance in some tests of learning and memory (Tang
et al. (1999) Nature 401: 63).
[0008] Conversely, decreased expression of selected NMDA receptor
sub-units in transgenic mice produces behaviors similar to
pharmacologically-induced animal models of schizophrenia, including
increased locomotion, increased stereotypy, and deficits in
social/sexual interactions (Mohn et al. (1999) Cell 98:427-436).
These aberrant behaviors can be ameliorated using the
antipsychotics haloperidol and clozapine.
[0009] NMDA receptors are widely distributed throughout the brain,
with a particularly high density in the cerebral cortex and
hippocampal formation.
[0010] Molecular cloning has revealed the existence of two classes
of glycine transporters in mammalian brains, termed GlyT-1 and
GlyT-2. GlyT-1 is found throughout the brain and spinal cord, and
it has been suggested that its distribution corresponds to that of
glutamatergic pathways and NMDA receptors (Smith, et al., Neuron,
8, 1992:927-935). Molecular cloning has further revealed the
existence of four variants of GlyT-1, termed GlyT-1a, GlyT-1b,
GlyT-1c and GlyT-1d. Two of these variants (1a and 1b) are found in
rodents, each of which displays a unique distribution in the brain
and peripheral tissues (Borowsky et al., Neuron, 10, 1993:851-863;
Adams et al., J. Neuroscience, 15, 1995:2524-2532). The third
variant, 1c, has only been detected in human tissues (Kim, et al.,
Molecular Pharmacology, 45, 1994:608-617). The fourth variant has
been detected in human tissues (see U.S. Pat. No. 6,008,015). These
variants arise by differential splicing and exon usage, and differ
in their N-terminal regions. GlyT-2, is found predominantly in the
brain stem and spinal cord, and its distribution corresponds
closely to that of strychnine-sensitive glycine receptors (Liu et
al., J. Biological Chemistry, 268, 1993:22802-22808; Jursky and
Nelson, J. Neurochemistry, 64, 1995:1026-1033). Another
distinguishing feature of glycine transport mediated by GlyT-2 is
that it is not inhibited by sarcosine as is the case for glycine
transport mediated by GlyT-1. These data are consistent with the
view that, by regulating the synaptic levels of glycine, GlyT-1 and
GlyT-2 selectively influence the activity of NMDA receptors and
strychnine-sensitive glycine receptors, respectively.
[0011] Compounds which inhibit or activate glycine transporters
would thus be expected to alter receptor function by modifying
glycine concentrations in the synapse and, thus, provide
therapeutic benefits in a variety of disease states.
[0012] For example, compounds which inhibit GlyT-1 mediated glycine
transport may increase glycine concentrations at NMDA receptors,
which receptors are located in the forebrain, among other
locations. This concentration increase could perhaps elevate the
activity of NMDA receptors, thereby possibly alleviating symptoms
of schizophrenia and enhancing cognitive function. Alternatively,
compounds that interact directly with the glycine receptor
component of the NMDA receptor can have the same or similar effects
as increasing or decreasing the availability of extracellular
glycine caused by inhibiting or enhancing GlyT-1 activity,
respectively. See, for example, Pitknen et al., Eur. J. Pharmacol.,
253, 125-129 (1994); Thiels et al., Neuroscience, 46, 501-509
(1992); and Kretschmer and Schmidt, J. Neurosci., 16, 1561-1569
(1996).
SUMMARY OF THE INVENTION
[0013] According to one aspect of the invention, there are provided
compounds of Formula I: 2
[0014] wherein:
[0015] R.sub.1 is selected from cycloalkyl, heterocycloalkyl, aryl
and heteroaryl;
[0016] wherein R.sub.1 is optionally substituted with one or more
substituents R.sub.a, wherein R.sub.a may be independently selected
from the group consisting of alkyl, halo, haloalkyl, nitro,
alkenyl, alkynyl, alkoxy, --(R.sub.7).sub.nNR.sub.8R.sub.9 (wherein
R.sub.7 is selected from alkyl, alkoxy, and oxyalkyl, R.sub.8 and
R.sub.9 can be independently selected from H, and alkyl, or R.sub.8
and R.sub.9 can join such that NR.sub.8R.sub.9 form a 5 or 6 member
heterocyclic ring, and n is selected from 0, and 1), and the
substituent R.sub.a is optionally further substituted with one or
more substituents selected from the group consisting of alkyl,
alkoxy, halo, cyano, alkanoyl, haloalkyl, thioalkyl, nitro, and
--(R.sub.7).sub.nNR.sub.8R.sub.9 wherein R.sub.7, R.sub.8, and
R.sub.9, and n are as defined above.
[0017] R.sub.2 and R.sub.3 are
[0018] a) independently selected from the group consisting of H,
alkyl, haloalkyl, aralkyl optionally substituted aryl, optionally
substituted heteroaryl and optionally substituted, saturated or
unsaturated, 5-or 6-membered, homocyclic or heterocyclic rings
wherein the optional substituent may be selected from the group
consisting of H, alkyl, alkoxy, and halo;
[0019] or
[0020] b) join together to form a 3, 4, 5, 6 or 7 member
spirocyclic ring;
[0021] X is selected from the group consisting of O, S, NH and
NCN;
[0022] Ar.sub.1 is phenyl and is optionally substituted with one or
more substituents R.sub.b,
[0023] wherein the substituents R.sub.b are independently selected
from the group consisting of alkyl, alkoxy, nitro, halo,
haloalkoxy, --(R.sub.7).sub.nNR.sub.8R.sub.9
--S(O).sub.2NR.sub.10R.sub.11, and
--O--(CH.sub.2).sub.mNR.sub.10R.sub.11 (wherein R.sub.7 is selected
from alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a 5 or 6 member
heterocyclic ring, and n is selected from 0, 1, 2, 3, 4 and 5 and
R.sub.10 and R.sub.11 can be independently selected from H, or
alkyl, or R.sub.10 and R.sub.11 can join together such that
NR.sub.10R.sub.11 form a 5 or 6 member heterocyclic ring and m is
selected from 1, 2, 3, 4, and 5 ) and;
[0024] the substituent R.sub.b is optionally further substituted
with one or more substituents selected from the group consisting of
alkyl, alkoxy, halo, cyano, alkanoyl, haloalkyl, thioalkyl, nitro,
--(R.sub.7).sub.nNR.sub.8R.sub.9 (wherein R.sub.7, R.sub.8, R.sub.9
and n are as described above), with the proviso that Ar.sub.1 does
not have a substituent at the 2-position selected from the
following groups, nitro haloalkyl, cyano, --C(O)R.sub.12
--C(O)OR.sub.12, --C(O)NR.sub.12R.sub.13- , --S(O)R.sub.12,
--S(O).sub.2R.sub.12, and --S(O).sub.2NR.sub.12R.sub.13 (wherein
R.sub.12 and R.sub.13 are independently selected from H and
alkyl),
[0025] and a second proviso that Ar.sub.1 does not have an alkanoyl
substituent at the 4 position,
[0026] and a salt solvate of hydrate thereof.
[0027] It has been found that compounds of Formula I inhibit
glycine transport via GlyT-1, or are precursors (for example,
pro-drugs) of such compounds. GlyT-1 transport inhibitors may be
useful in the treatment of schizophrenia, as well as other
CNS-related disorders such as cognitive dysfunction, dementia
(including that related to Alzheimer's disease), attention deficit
disorder, depression and intestinal disorders.
[0028] According to another aspect of the invention, there is
provided a pharmaceutical composition comprising a compound of
Formula I in an amount effective to inhibit glycine transport, and
a pharmaceutically acceptable carrier.
[0029] In another aspect of the invention, there are provided
compositions containing compounds of Formula 1 in amounts suitable
for pharmaceutical use to treat medical conditions for which a
glycine transport inhibitor is indicated. Preferred are those
compositions containing compounds useful in the treatment of
medical conditions for which GlyT-1-mediated inhibition of glycine
transport is needed, such as the treatment of schizophrenia,
cognitive dysfunction, or Alzheimer's.
[0030] Definitions
[0031] The term "aryl" as used herein means a 5, 6, 7, 8, 9 or 10
member monocyclic, bicyclic, or benzo-fused aromatic group such as
phenyl, naphthyl, indanyl, tetrahydronaphthyl, dihydronaphthyl,
indenyl and the like.
[0032] The term "heteroatom" as used herein means a non-carbon atom
such as S, N, O and the like.
[0033] The term "heteroaryl" as used herein means an aryl group
containing 1, 2 or 3 heteroatoms selected from N, O and S with the
proviso that no two like heteroatoms are adjacent unless both are
N, and includes such compounds as pyridyl, furyl, thienyl,
pyrimidinyl, pyrollyl, imidazolyl, triazolyl, oxazolyl, thiazolyl,
oxadiazolyl, thiadiazolyl, quinolinyl, quinoxylinyl, quinazolinyl,
pyrazinyl, pyrimidinyl, indolyl, indazolyl, azaindazolyl,
isoquinolinyl, and the like.
[0034] The term "alkyl" as used herein means straight- and
branched-chain alkyl radicals containing from 1, 2, 3, 4, 5 or 6
carbon atoms and includes methyl, ethyl, proplyl, isopropyl, butyl,
s-butyl, t-butyl n-pentyl, l-pentyl, neopentyl, hexyl, and the
like.
[0035] The term "cycloalkyl" as used herein means a carbocyclic
ring containing 3, 4, 5, 6, 7 or 8 carbon atoms and includes
cyclopropyl, cyclopentyl, cyclohexyl cycloheptyl, cyclooctyl and
the like.
[0036] The term "heterocycloalkyl" as used herein means a 3, 4, 5,
6, 7 or 8-membered ring containing one or two heteroatoms selected
from the group consisting of N, S, and O and includes piperidinyl,
piperazinyl, tetrahydopyran, tetrahydrothiopyran, morpholine
thiomorpholine, tetrahydrofuran, tetrahydrothiophene, pyrolidine,
and the like.
[0037] The term "alkoxy" as used herein means straight- and
branched-chain alkoxy radicals containing 1, 2, 3, 4, 5 or 6 carbon
atoms and includes methoxy, ethoxy, propoxy, isopropoxy, butoxy,
tertbutoxy, pentoxy, hexyloxy and the like.
[0038] The term "aralkyl" as used herein means an alkyl radical as
previously described substituted with an aryl group as previously
described and includes benzyl, phenethyl and the like.
[0039] The term "aralkoxy" as used herein means an alkoxy radical
substituted with an aryl group such as benzyloxy, phenethyloxy and
the like.
[0040] The term "aryloxy" as used herein means an aryl substituted
oxy radical such as phenoxy.
[0041] The terms "alkylene", "alkenylene" and "alkynylene" as used
herein means straight- and branched-chain bivalent radicals
containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene,
ethylene, 2-butenyl, vinyl, propenylene and ethynylene.
[0042] The term "alkanoyl" as used herein means straight- and
branched-chain radicals containing 1, 2, 3, 4, 5 or 6 carbon atoms
and includes acetyl, ethanoyl, propionyl, butanoyl, pentanoyl,
hexanoyl and the like.
[0043] The term "halo" as used herein means halogen and includes
fluoro, chloro, bromo and iodo.
[0044] The term "haloalkyl" as used herein means a straight or
branched chain alkyl radical of 1, 2, 3, 4, 5 or 6 carbons with one
or more halogen susbtituents such as trifluoromethyl, bromoethyl,
chloromethyl, chlorohexyl and the like.
[0045] The term "thioalkyl" as used herein means straight- and
branched-chain alkyl containing 1, 2, 3, 4, 5 or 6 carbons bonded
through a sulfur radical and includes thiomethyl (CH.sub.3S--),
thioethyl, thiopropyl thiobutyl, thiophenyl, thiohexyl and the
like.
[0046] The term "sulfonamido" as used herein means sulfonamide
radicals where the nitrogen may be unsubstituted or substituted or
a member of a ring and includes --S(O).sub.2NRR, wherein R can be
H, alkyl, alkoxy, cycloalkyl, aryl, and the like or the two R
groups may join together such that NRR forms a ring.
[0047] The term "SPE tube" as used herein refers to a solid phase
extraction tube. These may be commercially prepared disposable tube
filled with Silica gel for carrying out chromatography. Such tubes
can be purchased from Varian and Supelco.
[0048] The term "pharmaceutically acceptable salt" means an acid
addition salt, which is compatible with the treatment of
patients.
[0049] A "pharmaceutically aceptable addition salt" is any
non-toxic organic or inorganic acid addition salt of the base
compounds represented by Formula 1 or any of Formula 1's
intermediates. Illustrative inorganic acids which form suitable
salts include hydrochloric, hydrobromic, sulfuric, and phosphoric
acid and acid metal salts such as sodium monohydrogen,
orthophosphate and potassium hydrogensulfate. Illustrative organic
acids which form suitable salts include the mono-, di-, and
tricarboxylic acids. Illustrative of such acids are for example
acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric,
fumaric, malic, tartaric, citric, ascorbic, maleic, hydromaleic,
benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic,
2-phenoxybenzoic, p-toluensulfonic acid and other sulfonic acids
such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
Either the mono- or di-acid salts can be formed and such salts can
exist in either a hydrated, solvated, or substantially anhydrous
form. In general, the acid addition salts of these compounds are
more soluble in water and various hydrophilic organic solvents, and
generally demonstrate higher melting points in comparison to their
free base forms. The selection criteria for the appropriate salt
will be known to one skilled in the art.
[0050] The term "solvate" as used herein means a compound of
Formula 1 wherein molecules of a suitable solvent are incorporated
in a crystal lattice. A suitable solvent is physiologically
tolerable at the dosage administered as the solvate. Examples of
suitable solvents are ethanol and the like.
[0051] The term "stereoisomers" is a general term for all isomers
of the individual molecules that differ only in the orientation of
their atoms in space. It includes mirror image isomers
(enantiomers), geometric isomers (cis/trans) and isomers of
compounds with more than one chiral centre that are not mirror
images of one another (diastereomers).
[0052] The term "treat" or "treating" means to alleviate symptoms,
eliminate the causation of the symptoms, either on a temporary or
permanent basis, or to prevent or slow the appearance of symptoms
of the named disorder or condition.
[0053] The term "therapeutically acceptable carrier" means a
non-toxic solvent, dispersant, excipient, adjuvant, or other
material which is mixed with the active ingredient in order to
permit the formation of a pharmaceutical composition, i.e., a
dosage form capable of administration to the patient.
DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS
[0054] Compounds of the invention include compounds of Formula 1.
Compounds of Formula 1 include those in which R.sub.1 is selected
from cycloalkyl, heterocycloalkyl, aryl and heteroaryl and R.sub.1
is optionally substituted. In suitable embodiments of the invention
R.sub.1 is optionally substituted and is selected from naphthalene
tetrahydronaphthalene or quinoline. In further embodiments of the
invention R.sub.1 is unsubstituted and selected from naphthalene
tetrahydronaphthalene or quinoline.
[0055] In another suitable embodiment of the invention R.sub.1 is
optionally substituted pyridine. In further embodiments of the
invention R.sub.1 is 3-pyridyl optionally substituted with alkyl or
haloalkyl groups. In still further embodiments of the invention the
substituent is at the 6 position, for example 6-methyl-3-pryridyl
or 6-trifluoromethyl-3-pyridyl.
[0056] In yet a further embodiment of the invention R.sub.1 is
optionally substituted phenyl wherein substituents R.sub.a, are
selected from alkyl, alkoxy, alkanoyl, halo,
--(R.sub.7).sub.nNR.sub.8R.sub.9, (wherein R.sub.7 is selected from
alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a 5 or 6 member
heterocyclic ring, and n is selected from 0 and 1), aryl, nitro,
alkeny, haloalkyl, haloalkoxy, thioalkyl, cyano, and substituted or
unsubstituted piperazinyl. In more particular embodiments, the
substituents R.sub.a are selected from the group consisting of
methyl, Br, Cl, trifluromethyl, nitro, ipropyl, vinyl, methoxy,
Et.sub.2N-, trifluromethoxy, methythio, ethyl, phenyl, cyano,
N-methylpiperazinyl.
[0057] In a further embodiment of the invention R.sub.1 is selected
from mono or di-substituted phenyl wherein the substituents, in
order of preference, are located at the 3 and 4 positions>the 4
position>the 3 position>the 3 and 5 position>the 2 and 6
position>the 2 position>the 2 and 3 position. In another
particular embodiment R.sub.1 is 4-chlorophenyl, or
3-trifluoromethylphenyl. In another particular embodiment R.sub.1
is 3,4-dimethylpheyl. In yet another particular embodiment R.sub.1
is indanyl.
[0058] Another aspect of the invention includes compounds of
Formula 1 wherein Ar.sub.1 is optionally substituted phenyl. In a
further embodiment of the invention Ar.sub.1 is optionally
substituted phenyl wherein the substituents R.sub.b are selected
from alkyl, alkoxy, nitro, halo, haloalkoxy,
--(R.sub.7).sub.nNR.sub.8R.sub.9 (wherein R.sub.7 is selected from
alkyl, alkoxy, and oxyalkyl, R.sub.8 and R.sub.9 can be
independently selected from H, and alkyl, or R.sub.8 and R.sub.9
can join together such that NR.sub.8R.sub.9 form a 5 or 6-member
heterocyclic ring, and n is selected from 0, 1, 2, 3, 4 and 5)
--S(O).sub.2NR.sub.10R.- sub.11, and
--O--(CH.sub.2).sub.mNR.sub.10R.sub.11 (wherein R.sub.10 and
R.sub.11 can be independently selected from H, or alkyl, or R10 and
R11 can join together such that NR.sub.10R.sub.11 form a 5 or
6-member heterocyclic ring and m is selected from 1, 2, 3, 4, and
5). The substituents R.sub.b are optionally further substituted
with one or more substituents selected from the group consisting of
alkyl, alkoxy, halo, cyano, alkanoyl, haloalkyl, thioalkyl, nitro
and --(R.sub.7).sub.nNR.sub.- 8R.sub.9, wherein R.sub.7, R.sub.8,
R.sub.9 and n are as defined above. Furthermore there is a proviso
that, for the compounds of the present invention, Ar.sub.1 does not
have a substituent at the 2-position selected from the following
groups, nitro haloalkyl, cyano, --C(O)R.sub.12 --C(O)OR.sub.12,
--C(O)NR.sub.12R.sub.13, --S(O)R.sub.12, --S(O).sub.2R.sub.12, and
--S(O).sub.2NR.sub.12R.sub.13 (wherein R.sub.12 and R.sub.13 are
independently selected from H and alkyl), and a second proviso that
Ar.sub.1 does not have an alkanoyl substituent at the 4
position.
[0059] In another embodiment of the invention Ar.sub.1 is mono or
di-substituted phenyl wherein the substituents, in order of
preference, are located at the 2 and 5 position>the 2 and 4
position>the 2 position>the 4 position>the 3 position, in
order of preference.
[0060] In a further embodiment Ar.sub.1 is substituted phenyl
wherein the substituents are selected independently from alkyl,
alkoxy, halo, alkanoyl, nitro, trifluromethyl and
--(R.sub.7).sub.nNR.sub.8R.sub.9. In yet a further embodiment
Ar.sub.1 is di-substituted phenyl with the substituents selected
from methoxy, nitro, F, Cl, ethoxy, trifluoromethyl,
N-methylpiperidinyl, N'N-dimethylsulphonamide,
(CH.sub.3).sub.2NCH.sub.2CH.sub.2O--, and acetyl. In still a
further embodiment of the invention R.sub.4 is di-substituted
phenyl with the substituents selected from nitro and MeO--. In a
further embodiment Ar.sub.1 is 2-methoxy-5-nitrophenyl.
[0061] In another embodiment of the invention R.sub.2 and R.sub.3
are independently selected from, H, alkyl, haloalkyl, aralkyl
optionally substituted aryl, and optionally substituted heteroaryl,
and optionally substituted, saturated or unsaturated 5, or 6-member
homocyclic or heterocyclic rings.
[0062] In another suitable embodiment of the invention R.sub.2 and
R.sub.3 are selected independently from H, phenyl, 3-thiophene,
s-butyl, 3,4-difluorophenyl, cyclohexyl, 3-trifuoromethylphenyl,
t-butyl, i-propyl, methyl, benzyl, trifuoromethyl. In yet another
suitable embodiment R.sub.2 is H and R.sub.3 is selected from
phenyl, 3-thiophene, s-butyl, 3,4-difluorophenyl, cyclohexyl,
3-trifuoromethylphenyl, t-butyl, i-propyl, methyl, benzyl,
trifuoromethyl. In yet a further embodiment R.sub.2 is H and
R.sub.3 is selected from phenyl and 3-thiophene. In still a further
embodiment of the invention R.sub.2 and R.sub.3 together form a 3,
5 or 6-member spirocyclic ring.
[0063] In a suitable embodiment of the invention X can be O, S, NH,
or NCN. In more suitable embodiments X is O or S.
[0064] Specific embodiments of the invention include, but are not
limited to, the following compounds of formula 1:
[0065]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(2-indanyl)-2-(3-thie-
nyl) acetamide E42.2
[0066]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylphenyl)--
2-phenyl acetamide E32.2
[0067]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylphenyl)-2-ph-
enyl acetamide E32.5
[0068]
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylphen-
yl)-2-phenyl acetamide E33.1
[0069]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(2-indanyl)-2-(3-thienyl)
acetamide E42.1
[0070]
(R)-2-[3-(2-nitro-5-methoxy-phenyl)-ureido]-N-(2-indanyl)-2-phenyl
acetamide E29.1
[0071]
(R)-2-[3-(2-nitro-5-methoxy-phenyl)-ureido]-N-(4-chlorophenyl)-2-ph-
enyl acetamide E4.1
[0072] and
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3-trifluromethyl-
phenyl)-2-phenyl acetamide E31.2
[0073] In another embodiment of the invention, the compound of
Formula I is provided in labeled form, such as radiolabeled form
(e.g. labeled by incorporation within its structure .sup.3H or
.sup.14C or by conjugation to .sup.125I). In a preferred aspect of
the invention, such compounds, which bind preferentially to GlyT-1,
can be used to identify GlyT-1 receptor ligands by techniques
common in the art. This can be achieved by incubating the receptor
or tissue in the presence of a ligand candidate and then incubating
the resulting preparation with an equimolar amount of radiolabeled
compound of the invention. GlyT-1 receptor ligands are thus
revealed as those that significantly occupy the GlyT-1 site and
prevent binding of the radiolabeled compound of the present
invention. Alternatively, GlyT-1 receptor ligand candidates may be
identified by first incubating a radiolabeled form of a compound of
the invention then incubating the resulting preparation in the
presence of the candidate ligand. A more potent GlyT-1 receptor
ligand will, at equimolar concentration, displace the radiolabeled
compound of the invention.
[0074] Acid addition salts of the compounds of Formula I are most
suitably formed from pharmaceutically acceptable acids, and include
for example those formed with inorganic acids e.g. hydrochloric,
sulphuric or phosphoric acids and organic acids e.g. succinic,
maleic, acetic or fumaric acid. Other non-pharmaceutically
acceptable salts e.g. oxalates may be used for example in the
isolation of compounds of Formula I for laboratory use, or for
subsequent conversion to a pharmaceutically acceptable acid
addition salt. Also included within the scope of the invention are
base addition salts such as sodium, potassium and ammonium salts,
solvates and hydrates of compounds of the invention.
[0075] The conversion of a given compound to a desired compound
salt is achieved by applying standard techniques, well known to one
skilled in the art.
[0076] Compounds which inhibit GlyT-1 mediated glycine transport
will increase glycine concentrations at NMDA receptors, which
receptors are located in the forebrain, among other locations. This
concentration increase elevates the activity of NMDA receptors,
thereby alleviating schizophrenia and enhancing cognitive function.
Alternatively, compounds that interact directly with the glycine
receptor component of the NMDA receptor can have the same or
similar effects as increasing or decreasing the availability of
extracellular glycine caused by inhibiting or enhancing GlyT-1
activity, respectively. See, for example, Pitknen et al., Eur. J.
Pharmacol., 253, 125-129 (1994); Thiels et al., Neuroscience, 46,
501-509 (1992); and Kretschmer and Schmidt, J. Neurosci., 16,
1561-1569 (1996).
[0077] For use in medicine, the compounds of the present invention
can be administered in a standard pharmaceutical composition. The
present invention therefore provides, in a further aspect,
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier and a Formula 3 compound or a pharmaceutically
acceptable salt, solvate or hydrate thereof, in an amount effective
to treat the target indication.
[0078] The compounds of the invention are, for instance,
administered orally, sublingually, rectally, nasally, vaginally,
topically (including the use of a patch or other transdermal
delivery device), by pulmonary route by use of an aerosol, or
parenterally, including, for example, intramuscularly,
subcutaneously, intraperitoneally, intraarterially, intravenously
or intrathecally. Administration can be by means of a pump for
periodic or continuous delivery. The compounds of the invention are
administered alone, or are combined with a
pharmaceutically-acceptable carrier or excipient according to
standard pharmaceutical practice. For the oral mode of
administration, the compounds of the invention are used in the form
of tablets, capsules, lozenges, chewing gum, troches, powders,
syrups, elixirs, aqueous solutions and suspensions, and the like.
In the case of tablets, carriers that are used include lactose,
sodium citrate and salts of phosphoric acid. Various disintegrants
such as starch, and lubricating agents such as magnesium stearate
and talc, are commonly used in tablets. For oral administration in
capsule form, useful diluents are lactose and high molecular weight
polyethylene glycols. If desired, certain sweetening and/or
flavoring agents are added. For parenteral administration, sterile
solutions of the compounds of the invention are usually prepared,
and the pHs of the solutions are suitably adjusted and buffered.
For intravenous use, the total concentration of solutes should be
controlled to render the preparation isotonic. For ocular
administration, ointments or droppable liquids may be delivered by
ocular delivery systems known to the art such as applicators or eye
droppers. Such compositions can include mucomimetics such as
hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose
or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or
benzylchromium chloride, and the usual quantities of diluents
and/or carriers. For pulmonary administration, diluents and/or
carriers will be selected to be appropriate to allow the formation
of an aerosol.
[0079] Suppository forms of the compounds of the invention are
useful for vaginal, urethral and rectal administrations. Such
suppositories will generally be constructed of a mixture of
substances that is solid at room temperature but melts at body
temperature. The substances commonly used to create such vehicles
include theobroma oil, glycerinated gelatin, hydrogenated vegetable
oils, mixtures of polyethylene glycols of various molecular weight
and fatty acid esters of polyethylene glycol. See, Remington's
Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, Pa.,
1980, pp. 1530-1533 for further discussion of suppository dosage
forms and other dosage forms. Analogous gels or creams can be used
for vaginal, urethral and rectal administrations.
[0080] Numerous administration vehicles will be apparent to those
of ordinary skill in the art, including without limitation slow
release formulations, liposomal formulations and polymeric
matrices.
[0081] Examples of pharmaceutically acceptable acid addition salts
for use in the present invention include those derived from mineral
acids, such as hydrochloric, hydrobromic, phosphoric,
metaphosphoric, nitric and sulfuric acids, and organic acids, such
as tartaric, acetic, citric, malic, lactic, fumaric, benzoic,
glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic
acids, for example. Examples of pharmaceutically acceptable base
addition salts for use in the present invention include those
derived from non-toxic metals such as sodium or potassium, ammonium
salts and organoamino salts such as triethylamine salts. Numerous
appropriate such salts will be known to those of ordinary
skill.
[0082] The physician or other health care professional can select
the appropriate dose and treatment regimen based on the subject's
weight, age, and physical condition. Dosages will generally be
selected to maintain a serum level of compounds of the invention
between about 0.01 .mu.g/cc and about 1000 .mu.g/cc, preferably
between about 0.1 .mu.g/cc and about 100 .mu.g/cc. For parenteral
administration, an alternative measure of preferred amount is from
about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01
mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to
about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be
administered. For oral administrations, an alternative measure of
preferred administration amount is from about 0.001 mg/kg to about
10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably
from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to
about 1 mg/kg). For administrations in suppository form, an
alternative measure of preferred administration amount is from
about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1
mg/kg to about 1 mg/kg.
[0083] For use in assaying for activity in inhibiting glycine
transport, eukaryokic cells, preferably QT-6 cells derived from
quail fibroblasts, have been transfected to express one of the
three known variants of human GlyT-1, namely GlyT-1a, GlyT-1b or
GlyT-1c, or human GlyT-2. The sequences of these GlyT-1
transporters are described in Kim et al., Molec. Pharm. 45:
608-617, 1994, excepting that the sequence encoding the extreme
N-terminal of GlyT-1a was merely inferred from the corresponding
rat-derived sequence. This N-terminal protein-encoding sequence has
now been confirmed to correspond to that inferred by Kim et al. The
sequence of the human GlyT-2 is described by Albert et al., U.S.
Pat. No. 919,653 issued July 1999, which is incorporated herein by
reference in its entirety. Suitable expression vectors include
pRc/CMV (Invitrogen), Zap Express Vector (Stratagene Cloning
Systems, LaJolla, Calif.; hereinafter "Stratagene"), pBk/CMV or
pBk-RSV vectors (Stratagene), Bluescript II SK +/- Phagemid Vectors
(Stratagene), LacSwitch (Stratagene), pMAM and pMAM neo (Clontech),
among others. A suitable expression vector is capable of fostering
expression of the included GlyT DNA in a suitable host cell,
preferably a non-mammalian host cell, which can be eukaryotic,
fungal, or prokaryotic. Such preferred host cells include
amphibian, avian, fungal, insect, and reptilian cells.
[0084] Compounds of the present invention (compounds of Formula 1)
can be made by the method shown in Scheme I starting from the
appropriate amino acid A. The amino acid A is Boc protected at the
Nitrogen atom to give the intermediate B. A method for carrying out
the Boc protection is shown as I in Scheme 1. The Boc protected
amino acid can then be reacted with a primary amine as in method 11
to give the amide intermediate C. The Boc group is then removed to
give the free amine D, which can then be reacted an with an
isocyanate or isothiocyanate to give the urea or thiourea product E
respectively. 3
EXAMPLES
[0085] General Procedures
[0086] I- Conversion of Amino acid A to Boc protected product B
[0087] To a round bottom flask was added the amino acid (1 eq.),
Et.sub.3N (5 eq.) 1 M NaOH (1 eq.) and CH.sub.3CN. The clear
solution was cooled down to 0.degree. C. and to it was added
(Boc).sub.2O. The reaction was warmed to room temperature and
stirred for four hours, during which time a white precipitate
formed. The reaction mixture was concentrated and the residue was
dissolved in EtOAc:water (1:1). The organic phase was washed with
water and the aqueous phases were combined and treated with 10% HCl
and then were extracted with EtOAc three times. The combined
organic phase was washed successively with water, brine, dried over
MgSO.sub.4, filtered and concentrated to yield the title
compound.
[0088] II- Formation of amide intermediate C from Boc protected
Amino Acid, B, and a primary Amine.
[0089] To a flame dried round bottom flask was added Boc
protected-amino acid and CH.sub.2Cl.sub.2 (5 mL). The clear
solution was cooled to 0.degree. C. and the primary amine (1 eq.)
was added followed by diisopropylethylamine (2 eq.) and
N,N-bis(2-oxo-3-oxazolidinyl)phosphonic chloride (1 eq.). The white
suspension was allowed to stir at 0.degree. C. under Argon for two
hours. The workup included pouring the clear reaction mixture into
ether (3 parts) and water (2 parts). The organic layer was
separated and was successively washed with 1 N NaHSO.sub.4, water,
sat. NaHCO.sub.3 and brine. It was dried over MgSO.sub.4, filtered
and concentrated to yield the title compound.
[0090] III- Boc-deprotection of amide C to give intermediate D
[0091] The intermediate amide C and formic acid (neat) were added
to a sealed vial. The vial was heated at 60.degree. C. in an oil
bath for forty minutes. After cooling, the reaction mixture was
concentrated and the residue was purified by an SPE tube using
first CH.sub.2Cl.sub.2:MeOH 98:2 followed by 95:5, 94:6, 93:7,
92:8, 90:10, 85:15, 80:20 and finally 100% MeOH to yield the title
compound.
[0092] IV- Formation of final product E from D and an isocyanate or
isothiocyanate.
[0093] The amine D (1 eq.), and the desired isocyanate or
isothiocyanate (1.2 eq.), triethylamine (1 drop) and acetone (2 mL)
were added to a sealed vial. The reaction was heated to 50.degree.
C. and was left stirring for four hours. The mixture was
concentrated and the crude product was purified by an SPE tube
using Hexanes:Ethyl Acetate (90:10), (80:20), (70:30), (60:40),
(50:50) and finally (40:60) as the eluent to yield the title
compound.
[0094] The compounds of examples 1 through 41 were made from the
indicated starting materials by the general synthetic procedures
described above unless otherwise noted.
[0095] Experimental
[0096] In the experimental section each experiment describes the
formation of a series of intermediate compounds (A, B, C, and D)
and the formation of one or more final products, E , by the
reaction of intermediate D with one or more reagents. When more
than one final product E is made from a particular intermediate D
the final products are given differentiating numbers after the
decimal point. (for example E1.1 and E1.2). While the general
scheme shows four steps for making the final product some of the
required intermediates were found to be commercially available. In
cases where an intermediate is commercially available the
experiment starts with that intermediate (not with A). For example
Experiment 1 begins with the commercially available intermediate C1
which is converted to D1 which is then reacted with two different
reagents to produce two different final products E1.1 and E1.2.
Finally some of the compounds were produced as single enantiomers
while others were produced as a mixture. The numbering system
indicates the (R) enantiomer with a * and the (S) enantiomer with
**.
[0097] Experiment 1:
[0098] B1 N-Tert-butoxycarbony DL-phenyl glycine 4
[0099] N-Tert-butoxycarbonyl DL-phenyl glycine was isolated as a
white solid (7.61 g, 92%) from DL-2-phenylglycine (5.0 g, 33.1
mmol), 1 N NaOH (132.4 mL, 132.4 mmol) and (BOC).sub.2O (19.0 mL,
82.7 mmol).
[0100] C1 tert-butyl
[1-(2-methylphenylcarbamoyl)-1-phenyl-methyl]-carbama- te 5
[0101] [(tert-butoxycarbonyl)amino](phenyl)acetic acid (2.50 g,
9.95 mmol) was dissolved in dry THF (27 mL) in a flame dried flask
under Argon. The solution was cooled to -50.degree. C. and
N-methylmorpholine (1.11 g, 10.95 mmol) and isobutylchloroformate
(1.50 g, 10.95 mmol) were added. The reaction was allowed to stir
at this temperature for 2.5 hours. N-methylmorpholine (1.20 g,
11.94 mmol) was added to o-toluidine in THF (3 mL). This solution
was added to the reaction and the reaction was stirred overnight at
which time it warmed to room temperature. The THF was then
evaporated and CH.sub.2Cl.sub.2 (250 mL) was added. The solution
was poured into a separatory funnel and NaHCO.sub.3 (sat.) was
added. The organic phase was isolated and washed with NaHCO.sub.3
(sat), water and brine. The organic layer was then dried over
Na.sub.2SO.sub.4, filtered and concentrated to yield a white solid
(3.32 g, 98%).
[0102] D1 2-Amino-N-(2-methylphenyl)-2-phenylacetamide 6
[0103] tert-butyl
[1-(2-methylphenylcarbamoyl)-1-phenyl-methyl]-carbamate (2.00 g,
5.88 mmol) was dissolved in formic acid (20 mL) and the solution
was allowed to stir for 2 hours at 50.degree. C. under Argon. The
flask was cooled to room temperature and the formic acid was
evaporated. The resultant oil was dissolved in CH.sub.2Cl.sub.2 and
poured into a separatory funnel. 1 N NaOH was added and the product
was extracted with CH.sub.2Cl.sub.2 three times. The combined
organic layers were washed with water and brine, dried over
NaSO.sub.4, filtered and concentrated. The resultant oil was
dissolved in a small amount of EtOAc and Hexane was added slowly.
The solution became cloudy and a white solid precipitated (780.0
mg, 56%). The mother liquor was removed by pipette and the solid
was washed with Hexane three times and was dried under vacuum.
[0104] E1.1
N-(2-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 7
[0105]
N-(2-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-phe-
nyl acetamide (18.3 mg, 38%) was isolated as an off white solid
from 2-Amino-N-(2-methylphenyl)-2-phenylacetamide (25.6 mg, 0.107
mmol) and 2-methoxy-5-nitrophenyl isothiocyanate (33.8 mg, 0.149
mmol).
[0106] E1.2
N-(2-methylphenyl)-2-[3-(3-fluorophenyl)-thioureido]-2-phenyl
acetamide 8
[0107]
N-(2-methylphenyl)-2-[3-(3-fluorophenyl)-thioureido]-2-phenyl
acetamide (5.9 mg, 14%) was isolated as a white solid from
2-Amino-N-(2-methylphenyl)-2-phenylacetamide (25.7 mg, 0.107 mmol)
and 3-fluorophenyl isothiocyanate (24.7 mg, 0.161 mmol).
[0108]
E1.3N-(2-methylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-phenyl
acetamide 9
[0109]
N-(2-methylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-phenyl
acetamide (18.1 mg, 38%) was isolated as a white solid from
2-Amino-N-(2-methylphenyl)-2-phenylacetamide (28.4 mg, 0.118 mmol)
and 2-methoxyphenyl isothiocyanate (31.7 mg, 0.177 mmol).
[0110] E1.4
N-(2-methylphenyl)-2-[3-(4-fluorophenyl)-thioureido]-2-phenyl
acetamide 10
[0111]
N-(2-methylphenyl)-2-[3-(4-fluorophenyl)-thioureido]-2-phenyl
acetamide (19.9 mg, 46%) was isolated as a white solid from
2-Amino-N-(2-methylphenyl)-2-phenylacetamide (26.1 mg, 0.109 mmol)
and 4-fluorophenyl isothiocyanate (25.1 mg, 0.164 mmol).
[0112] E1.5
N-(2-methylphenyl)-2-[3-(3-methoxyphenyl)-thioureido]-2-phenyl
acetamide 11
[0113]
N-(2-methylphenyl)-2-[3-(3-methoxyphenyl)-thioureido]-2-phenyl
acetamide (40.6 mg, 76%) was isolated as a white solid from
2-Amino-N-(2-methylphenyl)-2-phenylacetamide (31.4 mg, 0.131 mmol)
and 3-methoxyphenyl thioisocyanate (35.3 mg, 0.197 mmol).
[0114] E1.6
N-(2-methylphenyl)-2-[3-(4-methoxyphenyl)-thioureido]-2-phenyl
acetamide 12
[0115]
N-(2-methylphenyl)-2-[3-(4-methoxyphenyl)-thioureido]-2-phenyl
acetamide (10.8 mg, 19%) was isolated as a white solid from
2-Amino-N-(2-methylphenyl)-2-phenylacetamide (33.4 mg, 0.139 mmol)
and 4-methoxyphenyl thioisocyanate (37.5 mg, 0.209 mmol).
[0116] E1.7 N-(2-methylphenyl)-2-[3-phenylthioureido]-2-phenyl
acetamide 13
[0117] N-(2-methylphenyl)-2-[3-phenylthioureido]-2-phenyl acetamide
was isolated as a white solid, (20.6 mg, 69%) from
phenylisothiocyanate (17 mg, 0.13 mmol) and
N-(2-methylphenyl)phenylglycinamide (20 mg, 0.08 mmol).
[0118] E1.8
N-(2-methylphenyl)-2-[3-(3-trifluoromethylphenyl)-thioureido]--
2-phenyl acetamide 14
[0119]
N-(2-methylphenyl)-2-[3-(3-trifluoromethylphenyl)-thioureido]-2-phe-
nyl acetamide was isolated as a white solid, (30 mg, 85%) from
3-trifluorophenylisothiocyanate (24 mg, 0.13 mmol) and
N-(2-methylphenyl)phenylglycinamide (20 mg, 0.08 mmol).
[0120] Experiment 2:
[0121] B2 1-(Tert-butoxycarbonylamino) cyclohexanecarboxylic acid
15
[0122] Tetramethylammonium hydroxide (1.27 g, 6.98 mmol) was added
to 1-amino-1-cyclohexane carboxylic acid (1.0 g, 6.98 mmol) in
CH.sub.3CN (20 mL). The mixture was allowed to stir for 45 minutes
at which time (Boc).sub.2O (3.05 g, 13.97 mmol) was added and the
reaction was allowed to stir at room temperature for three hours.
The solvent was then evaporated and Et.sub.2O was added. The
Et.sub.2O layer was extracted with water twice. The combined water
layers were then acidified with 10% HCl and EtOAc was added. The
product was extracted with EtOAc three times. The combined EtOAc
layers were washed with brine, dried over Na.sub.2SO.sub.4,
filtered and concentrated to yield the title compound (630.0 mg,
37%) as a white solid.
[0123] C2 Tert butyl-[1-(2-cyclohexyl-carbamoyl)-1-phenylmethyl]
carbamate 16
[0124] To a round bottom flask was added
1-(Tert-butoxycarbonylamino) cyclohexanecarboxylic acid (630.0 mg,
2.59 mmol), o-toluidine (0.31 g, 2.85 mmol) and 1 -methylimidazole
(0.43 g, 5.19 mmol) in DMF (15 mL) under Argon.
Diethylcyanophosphonate was added dropwise while the flask was
cooled in ice. The reaction was allowed to stir for three days
during which time it warmed to room temperature. NaHCO.sub.3 (sat)
was added and a white precipitate formed. The reaction was poured
into a separatory funnel and 1 M NaHSO.sub.4 was added and the
precipitate dissolved. The product was extracted with EtOAc three
times and the combined organic layers were washed with brine, dried
over NaSO.sub.4, filtered and concentrated. The crude product was
purified by column chromatography (15% EtOAc in Hexanes) to yield
the title compound (230 mg, 27%) as a white solid.
[0125] D2 1-Amino-N-(2-methylphenyl)cyclohexane carboxamide 17
[0126] 1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (564.0 mg,
79%) was isolated as a white solid from 1 -tert
butyl-N-(2-methylphenyl)cycloh- exane carbamate (0.850 g, 2.56
mmol).
[0127] E2.1 [1-(3-fluorophenyl)-thioureido
N-(2-methylphenyl)]-cyclohexane carboxamide 18
[0128] 1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (22.1 mg,
0.144 mmol) was dissolved in CH.sub.2Cl.sub.2 (1.0 mL) and
Et.sub.3N (1.0 mL) was added followed by
3-fluorophenylisothiocyanate (22.1 mg, 0.144 mmol) . The reaction
was allowed to stir at 40.degree. C. for three hours. EtOAc was
added (.about.20 mL) and the reaction was poured into a separatory
funnel. 1 M HCl was added and the aqueous layer was extracted with
EtOAc three times. The combined organic layers were washed with
brine, dried over NaSO.sub.4, filtered and concentrated. The crude
product was purified by an SPE tube using 50% EtOAc in hexanes as
the eluent to yield the title compound (4.2 mg, 15%) as a yellow
film.
[0129] E2.2
[1-(4-nitrophenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide 19
[0130] 1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (20.4 mg,
0.073 mmol) was dissolved in CH.sub.2Cl.sub.2 (2.0 mL) and
Et.sub.3N (8.9 mg, 0.088 mmol) was added followed by 4-nitrophenyl
isothiocyanate (15.9 mg, 0.088 mmol). The reaction was allowed to
stir in a sealed tube for three hours. The reaction was then
concentrated and purified by an SPE tube using first 30%
EtOAc/Hexanes followed by 50% EtOAc/Hexanes followed by 100% EtOAc.
The title compound was isolated as a yellow solid (6.6 mg,
22%).
[0131] E2.3
[1-(3-nitrophenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide 20
[0132]
[1-(3-nitrophenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide (21.5 mg, 74%) was isolated as a yellow solid from
1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (19.4 mg, 0.070
mmol) and 3-nitrophenyl isothiocyanate (15.1 mg, 0.084 mmol).
[0133] E2.4
[1-(4-methoxyphenyl)-thioureido]-N-(2-methylphenyl)-cyclohexan- e
carboxamide 21
[0134]
[1-(4-methoxyphenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide (14.0 mg, 32%) was isolated as an off white solid from
1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (30.5 mg, 0.110
mmol) and 4-methoxyphenylisothiocyanate (21.8 mg, 0.132 mmol).
[0135] E2.5
[1-(2-fluorophenyl)-thioureido-N-(2-methylphenyl)]cyclohexane
carboxamide 22
[0136]
[1-(2-fluorophenyl)-thioureido-N-(2-methylphenyl)]cyclohexane
carboxamide (5.6 mg, 16%) was isolated as brown solid from
1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (25.4 mg, 0.091
mmol) and 2-fluorophenyl isothiocyanate (27.8 mg, 0.182 mmol).
[0137] E2.6
[1-(4-fluorophenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide 23
[0138]
[1-(4-fluorophenyl)-thioureido]-N-(2-methylphenyl)-cyclohexane
carboxamide (2.9 mg, 10%) from
1-Amino-N-(2-methylphenyl)cyclohexane carboxamide (20.6 mg, 0.074
mmol) and 4-fluorophenyl isothiocyanate (22.7 mg, 0.148 mmol).
[0139] Experiment 3:
[0140] C3 tert-butyl
[1-(3-chlorophenylcarbamoyl)-1-phenyl-methyl]-carbama- te 24
[0141] tert-butyl
[1-(3-chlorophenylcarbamoyl)-1-phenyl-methyl]-carbamate was
isolated as a white solid (289.5 mg, 81%) from N-
Tert-butoxycarbonyl DL-phenyl glycine (250.0 mg, 0.99 mmol),
N-methylmorpholine (0.12 mL, 1.09 mmol), isobutylchloroformate
(0.14 mL, 1.09 mmol), 3-chloroaniline (0.13 mL, 1.19 mmol) and
N-methylmorpholine (0.13 mL, 1.19 mmol).
[0142] D3 2-Amino-N-(3-chlorophenyl)-2-phenylacetamide 25
[0143] 2-Amino-N-(3-chlorophenyl)-2-phenylacetamide was isolated as
a white solid (138.6 mg, 62%) from tert-butyl
[1-(4-chlorophenylcarbamoyl)-- 1-phenyl-methyl]-carbamate (280.2
mg, 0.86 mmol).
[0144] E3.1
N-(3-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 26
[0145]
N-(3-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-phe-
nyl 10 acetamide was isolated as a light yellow solid (21.9 mg,
58%) from 2-Amino-N-(3-chlorophenyl)-2-phenylacetamide (20.0 mg,
0.08 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (21.0 mg, 0.10
mmol).
[0146] Experiment 4:
[0147] C4 tert-butyl
[1-(4-chlorophenylcarbamoyl)-1-phenyl-methyl]-carbama- te 27
[0148] tert-butyl
[1-(4-chlorophenylcarbamoyl)-1-phenyl-methyl]-carbamate was
isolated as a white solid (266.2 mg, 74%) from
N-Tert-butoxycarbonyl DL-phenyl glycine (250.0 mg, 0.99 mmol),
N-methylmorpholine (0.12 mL, 1.09 mmol), isobutylchloroformate
(0.14 mL, 1.09 mmol), 4-chloroaniline 9152.3 mg, 1.19 mmol) and
N-methylmorpholine (0.13 mL, 1.19 mmol).
[0149] D4 2-Amino-N-(4-chlorophenyl)-2-phenylacetamide 28
[0150] 2-Amino-N-(4-chlorophenyl)-2-phenylacetamide was isolated as
a white solid (150.3 mg, 72%) from tert-butyl
[1-(4-chlorophenylcarbamoyl)-- 1-phenyl-methyl]-carbamate (259.6
mg, 0.80 mmol).
[0151] E4.1
N-(4-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 29
[0152]
N-(4-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-phe-
nyl acetamide was isolated as a light yellow solid (20.0 mg, 53%)
from 2-Amino-N-(4-chlorophenyl)-2-phenylacetamide (20.0 mg, 0.08
mmol) and 2-methoxy-5-nitrophenylisothiocyanate (21.0 mg, 0.10
mmol).
[0153] E4.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-chlorophenyl)-2-p-
henyl acetamide 30
[0154]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-chlorolphenyl)-2-pheny-
l acetamide (25.2 mg, 95.5%); from
2-Amino-N-(4-chlorophenyl)-2-phenylacet- amide (15 mg, 0.058
mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg,
0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0155] C4* R-tert-butyl
[1-(4-chlorophenylcarbamoyl)-1-phenyl-methyl]-carb- amate 31
[0156] R-tert-butyl
[1-(4-chlorophenylcarbamoyl)-1-phenyl-methyl]-carbamat- e was
isolated as a white solid (342.2 mg) from N-Tert-butoxycarbonyl
D-phenyl glycine (600.0 mg, 2.39 mmol), N-methylmorpholine (0.288
mL, 2.62 mmol), isobutylchloroformate (0.339 mL, 2.62 mmol),
4-chloroaniline (418 mg, 3.144 mmol) and N-methylmorpholine (0.318
mL, 3.144 mmol) and THF (2 ml).
[0157] D4* R-2-Amino-N-(4-chlorophenyl)-2-phenylacetamide 32
[0158] R-2-Amino-N-(4-chlorophenyl)-2-phenylacetamide was isolated
as a white solid (484.6 mg) from R-tert-butyl
[1-(4-chlorophenylcarbamoyl)-1-p- henyl-methyl]-carbamate (342.2
mg) and Formic acid (2 ml).
[0159] E4.1*
R-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-chlorophenyl)--
2-phenyl acetamide 33
[0160]
R-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-chlorolphenyl)-2-phe-
nyl acetamide (280.0 mg, 53.4%); from
R-2-Amino-N-(4-chlorophenyl)-2-pheny- lacetamide (300 mg, 1.151
mmoles) reacted with 2-methoxy-5-nitrophenylisoc- yanate (290 mg,
1.495 mmoles) in dichloromethane (10 ml) at 60.degree. C.
overnight.
[0161] Experiment 5:
[0162] C5 tert-butyl
[1-(2.3-dimethylphenylcarbamoyl)-1-phenyl-methyl]-car- bamate
34
[0163] tert-butyl
[1-(2,3-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate was
isolated as a white solid (230.5 mg, 66%) from BOC-phenylglycine
(250.0 mg, 0.99 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol),
isobutylchloroformate (0.14 mL, 1.09 mmol), 2,3-dimethylaniline
(0.15 mL, 1.19 mmol) and N-methylmorpholine (0.13 mL, 1.19
mmol).
[0164] D5 2-Amino-N-(2,3-dimethylphenyl)-2-phenylacetamide 35
[0165] 2-Amino-N-(2,3-dimethylphenyl)-2-phenylacetamide was
isolated as a white solid (118.6 mg, 75%) from tert-butyl
[1-(2,3-dimethylphenylcarbamo- yl)-1-phenyl-methyl]-carbamate
(220.4 mg, 0.62 mmol).
[0166] E5.1
N-(2,3-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide 36
[0167]
N-(2,3-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-
-phenyl acetamide was isolated as a light yellow solid (16.7 mg,
60%) from 2-Amino-N-(2,3-dimethylphenyl)-2-phenylacetamide (14.6
mg, 0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (915.7 mg,
0.07 mmol).
[0168] Experiment 6:
[0169] C6 tert-butyl
[1-(5,6,7,8-tetrahydro-1-naphthylcarbamoyl)-1-phenyl--
methyl]-carbamate 37
[0170] tert-butyl
[1-(5,6,7,8-tetrahydro-1-naphthylcarbamoyl)-1-phenyl-met-
hyl]-carbamate was isolated as a white solid (299.8 mg, 80%) from
BOC-phenyl glycine (250.0 mg, 0.99 mmol), N-methylmorpholine (0.12
mL, 1.09 mmol), isobutylchloroformate (0.14 mL, 1.09 mmol),
5,6,7,8-tetrahydro-1-naphthlamine (175.8 mg, 1.19 mmol) and
n-methylmorpholine (0.13 mL, 1.19 mmol).
[0171] D6 2-Amino-N-(5,6.7,8-tetrahydronaphthyl)-2-phenylacetamide
38
[0172] 2-Amino-N-(5,6,7,8-tetrahydronaphthyl)-2-phenylacetamide was
isolated as a white solid (147.9 mg, 70%) from tert-butyl
[1-(5,6,7,8-tetrahydro-1-naphthylcarbamoyl)-1-phenyl-methyl]-carbamate
(286.9 mg, 0.75 mmol).
[0173] E6.1
N-(5,6,7,8,-tetrahydronaphthyl)-2-[3-(2-methoxy-5-nitrophenyl)-
-thioureido]-2-phenyl acetamide 39
[0174]
N-(5,6,7,8,-tetrahydronaphthyl)-2-[3-(2-methoxy-5-nitrophenyl)-thio-
ureido]-2-phenyl acetamide was isolated as a light yellow solid
(19.2 mg, 65%) from
2-Amino-N-(5,6,7,8,-tetrahydronaphthyl)-2-phenylacetamide (16.1 mg,
0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (15.7 mg, 0.07
mmol).
[0175] Experiment 7:
[0176] C7 tert-butyl
[1-(2-methyl-4-chlorophenylcarbamoyl)-1-phenyl-methyl- ]-carbamate
40
[0177] tert-butyl
[1-(2-methyl-4-chlorophenylcarbamoyl)-1-phenyl-methyl]-c- arbamate
was isolated as white solid (296.7 mg, 80%) from BOC-phenylglycine
(250.0 mg, 0.99 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol),
isobutylchloroformate (0.14 mL, 1.09 mmol),
-2-methyl-4-chloroaniline (169.1 mg, 1.19 mmol) and
N-methylmorpholine (0.13 mL, 1.19 mmol).
[0178] D7 2-Amino-N-(2-methyl-4-chlorophenyl)-2-phenylacetamide
41
[0179] 2-Amino-N-(2-methyl-4-chlorophenyl)-2-phenylacetamide was
isolated as a white solid (148.3 mg, 71%) from tert-butyl
[1-(2-methyl-4-chlorophe- nylcarbamoyl)-1-phenyl-methyl]-carbamate
(284.6 mg, 0.76 mmol).
[0180] E7.1
N-(2-methyl-4-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thi-
oureido]-2-phenyl acetamide 42
[0181]
N-(2-methyl-4-chlorophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide was isolated as a light yellow solid (19.0
mg, 65%) from 2-Amino-N-(2-methyl-4-chlorophenyl)-2-phenylacetamide
(15.8 mg, 0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate
(15.7 mg, 0.07 mmol).
[0182] Experiment 8:
[0183] C8 tert-butyl
[1-(2-ethyl-6-methylphenylcarbamoyl)-1-phenyl-methyl]- -carbamate
43
[0184] tert-butyl
[1-(2-ethyl-6-methylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
was isolated as a white solid (236.6 mg, 65%) from
BOC-phenylglycine (250.0 mg, 0.99 mmol), N-methylmorpholine (0.12
mL, 1.09), isobutylchloroformate (0.14 mL, 1.09 mmol),
6-ethyl-o-toluidine (0.17 mL, 1.19 mmol) and N-methylmorpholine
(0.13 mL, 1.19 mmol).
[0185] D8 2-Amino-N-(2-ethyl-6-methylphenyl)-2-phenylacetamide
44
[0186] 2-Amino-N-(2-ethyl-6-methylphenyl)-2-phenylacetamide was
isolated as a white solid (83.5 mg, 50%) from tert-butyl
[1-(2-ethyl-6-methylpheny- lcarbamoyl)-1-phenyl-methyl]-carbamate
(228.2 mg, 0.62 mmol).
[0187] E8.1
N-(2-ethyl-6-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thio-
ureido]-2-phenylacetamide 45
[0188]
N-(2-ethyl-6-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureid-
o]-2-phenyl acetamide was isolated as a yellow solid (22.3 mg, 78%)
from 2-Amino-N-(2-ethyl-6-methylphenyl)-2-phenylacetamide (15.8 mg,
0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (14.9 mg, 0.07
mmol).
[0189] Experiment 9:
[0190] C9 tert-butyl
[1-(2-isopropyl-6-methylphenylcarbamoyl)-1-phenyl-met-
hyl]-carbamate 46
[0191] tert-butyl
[1-(2-isopropyl-6-methylphenylcarbamoyl)-1-phenyl-methyl-
]-carbamate was isolated as a white solid (216.1 mg, 57%) from
BOC-phenylglycine (250.0 mg, 0.99 mmol), N-methylmorpholine (0.12
mL, 1.09 mmol), isobutylchloroformate (0.14 mL, 1.09 mmol),
2-isopropyl-6-methylaniline (0.19 mL, 1.19 mmol) and
N-methylmorpholine (0.13 mL, 1.19 mmol).
[0192] D9 2-Amino-N-(2-isopropyl-6-methylphenyl)-2-phenylacetamide
47
[0193] 2-Amino-N-(2-isopropyl-6-methylphenyl)-2-phenylacetamide was
isolated as a white solid (78.8 mg, 51%) from tert-butyl
[1-(2-isopropyl-6-methylphenylcarbamoyl)-1-phenyl-methyl]-carbamate
(210.0 mg, 0.55 mmol).
[0194] E9.1
N-(2-isopropyl-6-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)--
thioureido]-2-phenyl acetamide 48
[0195]
N-(2-isopropyl-6-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiou-
reido]-2-phenyl acetamide was isolated as a yellow solid (15.3 mg,
52%) from 2-Amino-N-(2-isopropyl-6-methylphenyl)-2-phenylacetamide
(16.7 mg, 0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate
(14.9 mg, 0.07 mmol).
[0196] Experiment 10:
[0197] C10 tert-butyl
[1-(2-chloro-6-methylphenylcarbamoyl)-1-phenyl-methy- l]-carbamate
49
[0198] tert-butyl
[1-(2-chloro-6-methylphenylcarbamoyl)-1-phenyl-methyl]-c- arbamate
was isolated as a white solid (139.2 mg, 38%) from
BOC-phenylglycine (250.0 mg, 0.99 mmol), N-methylmorpholine (0.12
mL, 1.09 mmol), isobutylchloroformate (0.14 mL, 1.09 mmol),
2-chloro-6-methylaniline (0.15 mL, 1.19 mmol) and
N-methylmorpholine (0.13 mL, 1.19 mmol).
[0199] D10 2-Amino-N-(2-chloro-6-methylphenyl)-2-phenylacetamide
50
[0200] 2-Amino-N-(2-chloro-6-methylphenyl)-2-phenylacetamide was
isolated as a white solid (37.9 mg, 38%) from tert-butyl
[1-(2-chloro-6-methylphen- ylcarbamoyl)-1-phenyl-methyl]-carbamate
(132.8 mg, 0.36 mmol).
[0201] E10.1
N-(2-chloro-6-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-th-
ioureido]-2-phenyl acetamide 51
[0202] acetamide was isolated as a yellow solid (14.8 mg, 76%) from
2-Amino-N-(2-chloro-6-methylphenyl)-2-phenylacetamide (10.0 mg,
0.04 mmol) and 2-methoxy-5-nitrophenyl isothiocyanate (9.2 mg, 0.04
mmol).
[0203] Experiment 11:
[0204] C11 tert-butyl
[1-(2,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
52
[0205] tert-butyl
[1-(2,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate was
isolated as a white solid (240.2 mg, 68%) from BOC-phenylglycine
(250.0 mg, 0.99 mmol), N-methylmorpholine (0.12 mL, 1.09 mmol),
isobutylchloroformate (0.14 mL, 1.09 mmol), 2,4-dimethylaniline
(0.15 mL, 1.19 mmol) and N-methylmorpholine (0.13 mL, 1.19
-mmol).
[0206] D11.1 2-Amino-N-(2,4-dimethylphenyl)-2-phenylacetamide
53
[0207] 2-Amino-N-(2,4-dimethylphenyl)-2-phenylacetamide was
isolated as a white solid (86.1 mg, 52%) from tert-butyl
[1-(2,4-dimethylphenylcarbamoy- l)-1-phenyl-methyl]-carbamate
(231.0 mg, 0.65 mmol).
[0208] E11
N-(2,4-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureid-
o]-2-phenyl acetamide 54
[0209]
N-(2,4-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-
-phenyl acetamide was isolated as a yellow solid (21.4 mg, 77%)
from 2-Amino-N-(2,4-dimethylphenyl)-2-phenylacetamide (15.0 mg,
0.06 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (7.9 mg, 0.038
mmol).
[0210] Experiment 12:
[0211] C12 tert-butyl
[1-(2,6-dimethylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
55
[0212] tert-butyl
[1-(2,6-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate was
isolated (1.61 g, 76%) from BOC-phenyl glycine (1.50 g, 5.97 mmol),
N-methylmorpholine (0.72 mL, 6.57 mmol), isobutylchloroformate
(0.85 mL, 6.57 mmol), 2,6-dimethylaniline (0.88 mL, 7.16 mmol) and
N-methylmorpholine (0.79 mL, 7.16 mmol).
[0213] D12 2-Amino-N-(2,6-dimethylphenyl)-2-phenylacetamide 56
[0214] 2-Amino-N-(2,6-dimethylphenyl)-2-phenylacetamide was
isolated as a white solid (717.2 mg, 67%) from tert-butyl
[1-(2,6-dimethylphenylcarbamo- yl)-1-phenyl-methyl]-carbamate (1.50
g, 4.24 mmol).
[0215] 4-chloro-3-nitro-(N-methyl)piperizinylphenylsulphonamide
57
[0216] 4-chloro-3-nitro-(N-methyl)piperizinylsulphonamide was
isolated as a light yellow solid (474.3 mg, 76%) from
4-chloro-3-nitrobenzene sulphonyl chloride (500.0 mg, 1.95 mmol)
and diisopropylethylamine (0.34 mL, 1.95 mmol) and
N-methylpiperizine (0.22 mL, 1.95 mmol).
[0217] 4-amino-3-nitro-(N-methyl)piperizinylphenylsulphonamide
58
[0218] 4-amino-3-nitro-(N-methyl) piperizinylsulphonamide was
isolated as a yellow solid (14.2 mg, 14%) from
4-chloro-3-nitro-(N-methyl)piperizinyl- phenylsulphonamide (110.5
mg, 0.35 mmol) and 2M NH.sub.3/MeOH (5 mL).
[0219] 1 -(N-methyl)piperizinyl
sulphonamido-3-nitro-4-phenylisothiocyanat- e 59
[0220] 1-(N-methyl)piperizinyl
sulphonamido-3-nitro-4-phenylisothiocyanate was isolated as a clear
yellow oil (1.8 mg, 13%) from 4-amino-3-nitro-(N-methyl)
piperizinylphenylsulphonamide (13.2 mg, 0.04 mmol) and DPT (10.2
mg, 0.04 mmol).
[0221] E12.1
N-(2,6-dimethylphenyl)-2-[3-(2-methyl-4-(N-methyl)piperizinyl
sulphonamidophenyl)-thioureido]-2-phenyl acetamide 60
[0222]
N-(2,6-dimethylphenyl)-2-[3-(2-methyl-4-(N-methyl)piperizinyl
suiphonamido phenyl)-thioureido]-2-phenyl acetamide was isolated
(3.1 mg, 103%) from
2-Amino-N-(2,6-dimethylphenyl)-2-phenylacetamide (1.3 mg, 0.005
mmol) and 1-(N-methyl) piperizinyl
sulphonamido-3-nitro-4-phenyliso- thiocyanate (1.8 mg, 0.005
mmol).
[0223] Experiment 13:
[0224] C13 tert-butyl
[1-(4-methylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate 61
[0225] tert-butyl
[1-(4-methylphenylcarbamoyl)-1-phenyl-methyl]-carbamate was
isolated as a white solid (1.88 g, 139%) from
[(tert-butoxycarbonyl)a- mino](phenyl)acetic acid (1.0 g, 3.98
mmol), N-methylmorpholine (0.48 mL, 4.38 mmol),
isobutylchloroformate (0.57 mL, 4.38 mmol) and 4-methylaniline
(0.51 g, 4.78 mmol)and N-methylmorpholine (0.52 mL, 4.78 mmol).
[0226] D13 2-Amino-N-(4-methylphenyl)-2-phenylacetamide 62
[0227] To a 50 mL round bottom flask equipped with a stirring bar
was added tert-butyl
[1-(4-methylphenylcarbamoyl)-1-phenyl-methyl]-carbamate (1.88 g,
5.52 mmol) and formic acid (15 mL). The reaction was stirred at
50.degree. C. for 1.5 hours after which it was cooled to room
temperature. The formic acid was removed in vacuo and the resulting
oil was taken up into EtOAc (75 mL) and water (75 mL). 1 N NaOH was
added until the pH was 8-9 and the aqueous layer was extracted with
EtOAc two additional times. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered and concentrated. The
crude product was purified by column chromatography (Hexanes:EtOAc
60:40 to CH.sub.2Cl.sub.2:MeOH 95:5 to yield the title compound as
an off white solid (874.2 mg, 91%).
[0228] E13.1
N-(4-methylphenyl)-2-[3-(1-naphthyl)-thioureido]-2-phenyl acetamide
63
[0229] N-(4-methylphenyl)-2-[3-(1-naphthyl)-thioureido]-2-phenyl
acetamide was isolated as a white solid (37.4 mg, 70%) from
2-Amino-N-(4-methylphen- yl)-2-phenylacetamide (30.3 mg, 0.13 mmol)
and 1-naphthylisothiocyanate (35.0 mg, 0.19 mmol).
[0230] E13.2
N-(2-(4-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide 64
[0231]
N-(2-(4-methylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2--
phenyl acetamide was isolated (21.0 mg, 38%) from
2-amino-N-(2-isopropylph- enyl)-2-phenylacetamide (30.0 mg, 0.124
mmol) and 2-methoxy-5-nitrophenyli- sothiocyanate (31.5 mg, 0.145
mmol).
[0232] E13.3
2-[3-(2-chloro-5-nitrophenyl)-thioureido]-N-(4-methylphenyl)--
2-phenyl acetamide 65
[0233]
2-[3-(2-chloro-5-nitrophenyl)-thioureido]-N-(4-methylphenyl)-2-phen-
yl acetamide (22.6 mg, 99%); from
2-Amino-N-(4-methylphenyl)-2-phenylaceta- mide (17 mg, 0.05 mmoles)
reacted with 2-chloro-5-nitrophenylisothiocyanat- e (16.3, 0.075
mmoles) in dichloromethane (0.8 ml) 60.degree. C.
[0234] E13.4
2-[3-(2-methoxy-5-methylphenyl)-thioureido]-N-(4-methylphenyl-
)-2-phenyl acetamide 66
[0235]
2-[3-(2-methoxy-5-methylphenyl)-thioureido]-N-(4-methylphenyl)-2-ph-
enyl acetamide (15.7 mg, 74.8%); from
2-Amino-N-(4-methylphenyl)-2-phenyla- cetamide (17 mg, 0.05 mmoles)
reacted with 2-methoxy-5-methylphenylisothio- cyanate (13.4, 0.075
mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
[0236] E13.5
2-[3-(5-chloro-2-methoxy-phenyl)-thioureido]-N-(4-methylpheny-
l)-2-phenyl acetamide 67
[0237]
2-[3-(5-chloro-2-methoxy-phenyl)-thioureido]-N-(4-methylphenyl)-2-p-
henyl acetamide (20.4 mg, 92.7%); from
2-Amino-N-(4-methylphenyl)-2-phenyl- acetamide (17 mg, 0.05 mmoles)
reacted with 5-chloro-2-methoxy-phenylisoth- iocyanate (15, 0.075
mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
[0238] E13.6
2-[3-(2,5-dimethoxy-phenyl)-thioureido]-N-(4-methylphenyl)-2--
phenyl acetamide 68
[0239]
2-[3-(2,5-dimethoxy-phenyl)-thioureido]-N-(4-methylphenyl)-2-phenyl
acetamide (22.4 mg, 72.4%); from
2-Amino-N-(4-methylphenyl)-2-phenylaceta- mide (17 mg, 0.05 mmoles)
reacted with 2,5-dimethoxy-phenylisothiocyanate (14.64, 0.075
mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
[0240] E13.7 2-[3-(
2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methylphenyl)-2- -phenyl
acetamide 69
[0241]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methylphenyl)-2-phenyl
acetamide (53.3 mg, 87.3%); from
2-Amino-N-(4-methylphenyl)-2-phenylaceta- mide (34 mg, 0.1 mmoles)
reacted with 2-methoxy-5-nitro-phenylisocyanate (23.3 mg, 0.12
mmoles) in dichloromethane (1.2 ml) at 60.degree. C.
[0242] E13.8
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methylphenyl-
)-2-phenyl acetamide and
(S)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4--
methylphenyl)-2-phenyl acetamide 70
[0243]
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methylphenyl)-2-ph-
enyl acetamide and
(S)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methyl-
phenyl)-2-phenyl acetamide were separated from
2-[3-(2-methoxy-5-nitro-phe-
nyl)-ureido]-N-(4-methylphenyl)-2-phenyl acetamide by chiracel OD
column with HPLC [ethanol(1% acetic acid): Hexane=20:80] 71
[0244] Experiment 14:
[0245] C14 tert-butyl
[1-(phenylcarbamoyl)-1-phenyl-methyl]-carbamate 72
[0246] tert-butyl [1-(phenylcarbamoyl)-1-phenyl-methyl]-carbamate
was isolated as a white solid (1.42 g, 110%) from
[(tert-butoxycarbonyl)amino- ](phenyl)acetic acid (1.0 g, 3.98
mmol), N-methylmorpholine (0.48 mL, 4.38 mmol),
isobutylchloroformate (0.57 mL, 4.38 mmol), aniline (0.44 mL, 4.78
mmol) and N-methylmorpholine (0.52 mL, 4.78 mmol).
[0247] D14 2-Amino-N-(phenyl)-2-phenylacetamide 73
[0248] 2-Amino-N-(phenyl)-2-phenylacetamide was isolated as a white
solid (754.5 mg, 84%) from tert-butyl
[1-(phenylcarbamoyl)-1-phenyl-methyl]-car- bamate (1.42 g, 4.36
mmol).
[0249] E14.1 N-(Phenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-phenyl
acetamide 74
[0250] N-(phenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-phenyl
acetamide was isolated as a white solid (28.9 mg, 56%) from
2-Amino-N-(phenyl)-2-ph- enylacetamide (29.7 mg, 0.13 mmol) and
2-methoxyphenylisothiocyanate (35.0 mg, 0.20 mmol).
[0251] E14.2 N-(Phenyl)-2-[3-(2-fluorophenyl)-thioureido]-2-phenyl
acetamide 75
[0252] N-(phenyl)-2-[3-(2-fluorophenyl)-thioureido]-2-phenyl
acetamide was isolated as a white solid (38.7 mg, 72%) from
2-Amino-N-(phenyl)-2-phenyl- acetamide (32.2 mg, 0.14 mmol) and
2-fluorophenylisothiocyanate (33.0 mg, 0.21 mmol).
[0253] Experiment 15:
[0254] C15 tert-butyl
[1-(3-methylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate 76
[0255] tert-butyl
[1-(3-methylphenylcarbamoyl)-1-phenyl-methyl]-carbamate was
isolated as an off-white solid (1.46 g, 108%) from
[(tert-butoxycarbonyl)amino](phenyl)acetic acid (1.0 g, 3.98 mmol),
N-methylmorpholine (0.48 mL, 4.38 mmol), isobutylchloroformate
(0.57 mL, 4.38 mmol), 3-methylaniline (0.52 mL, 4.78 mmol) and
N-methylmorpholine (0.52 mL, 4.78 mmol).
[0256] D15 2-Amino-N-(3-methylphenyl)-2-phenylacetamide 77
[0257] 2-Amino-N-(3-methylphenyl)-2-phenylacetamide was isolated as
an off-white solid (917.1 mg, 96%) from tert-butyl
[1-(3-methylphenylcarbamo- yl)-1-phenyl-methyl]-carbamate (1.46 g,
4.29 mmol).
[0258] E15.1
N-(3-methylphenyl)-2-[3-(2-fluorophenyl)-thioureido]-2-phenyl
acetamide 78
[0259]
N-(3-methylphenyl)-2-[3-(2-fluorophenyl)-thioureido]-2-phenyl
acetamide was isolated as pale yellow solid (31.6 mg, 63%) from
2-Amino-N-(3-methylphenyl)-2-phenylacetamide (30.4 mg, 0.13 mmol)
and 2-fluorophenylisothiocyanate (29.0 mg, 0.19 mmol).
[0260] E15.2
N-(3-methylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-pheny- l
acetamide 79
[0261]
N-(3-methylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-phenyl
acetamide was isolated as a white solid (19.7 mg, 38%) from
2-Amino-N-(3-methylphenyl)-2-phenylacetamide (30.9 mg, 0.13 mmol)
and 2-methoxyphenylisothiocyanate (34.5 mg, 0.19 mmol). 80
[0262] Experiment 16:
[0263] E16.1
N-(2-(2-isopropylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-
-phenyl acetamide 81
[0264]
N-(2-(2-isopropylphenyl)-2-[3-(2-methoxyphenyl)-thioureido]-2-pheny-
l acetamide was isolated (13.0 mg, 27%) from
2-amino-N-(2-isopropylphenyl)- -2-phenylacetamide (30.0 mg, 0.111
mmol) and 2-methoxyphenylisothiocyanate (30.0 mg, 0.166 mmol).
[0265] Experiment 17:
[0266] E17.1
N-(2-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-
-thioureido]-2-(2,3-difluoro)phenyl acetamide 82
[0267]
N-(2-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiou-
reido]-2-(2,3-difluoro)phenyl acetamide was isolated (17.7 mg, 60%)
from 2-amino-N-(4-trifluoromethylphenyl)-2-(3,4-difluoro)
phenylacetamide (20.0 mg, 0.061 mmol) and
2-methoxy-5-nitroisothiocyanate (19.0 mg, 0.090 mmol).
[0268] Experiment 18:
[0269] E18.1
N-(2-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-
-thioureido]-2-(3-trifluoromethyl)phenyl acetamide 83
[0270]
N-(2-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiou-
reido]-2-(3-trifluoromethyl)phenyl acetamide was isolated (20.0 mg,
81%) from 2-amino-N-(4-trifluoromethylphenyl)-2-(3-trifluoromethyl)
phenylacetamide (20.0 mg, 0.055 mmol) and
2-methoxy-5-nitrophenylisothioc- yanate (18.0 mg, 0.082 mmol).
[0271] Experiment 19:
[0272] C19 tert-butyl
[1-(4-isopropylphenylcarbamoyl)-1-phenyl-methyl]-car- bamate 84
[0273] To the mixture of [(tert-butoxycarbonyl)amino](phenyl)acetic
acid (500 mg, 2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2
mmoles) in THF (5 ml) at -40.about.-50.degree. C. was added
isobutyl chloroformate (235 .mu.l, 2.2 mmoles). After the reaction
mixture was stirred for 2 hours, a mixture of 4-isopropylaniline
(325 mg, 2.4 mmoles) and N-methylmorpholine (263 ml, 2.4 mmoles)
were added. After the reaction mixture was stirred and left
overnight, it was diluted with dichloromethane (20 ml) and washed
with water (20 ml), 1 M sodium hydrosulphate (20 ml X 3) and brine
(20 ml), dried with sodium sulfate, concentrated. The residue was
triturated with hexanes to give the white solid tert-butyl
[1-(4-isopropylphenylcarbamoyl)-1-phenyl-methyl]-carbamate (577 mg,
yield 78.7%).
[0274] D19 2-Amino-N-(4-isopropylphenyl)-2-phenylacetamide formic
acid salt 85
[0275] tert-butyl
[1-(4-isopropylphenylcarbamoyl)-1-phenyl-methyl]-carbama- te (500
mg, 1.36 mmoles) was mixed with 96% formic acid (5 ml) and heated
to 60.degree. C. for 0.5 hour. The reaction mixture was
concentrated by evaporation. The residue was triturated with
hexanes and ether (1:1, 10 ml) to give the white solid product,
2-Amino-N-(4-isopropylphenyl)-2-phen- ylacetamide formic acid salt
(426 mg, quantitative).
[0276] E19.1
N-(4-isopropylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide 86
[0277] 2-Amino-N-(4-isopropylphenyl)-2-phenylacetamide formic acid
salt (15.6 mg, 0.05 mmoles) was mixed with
2-methoxy-5-nitrophenylthioisocyana- te (12.6 mg, 0.06 mmoles) and
triethylamine (15.2 mg, 0.15 mmoles) in dichloromethane (1 ml) at
ambient temperature. The reaction was stirred overnight. The
solvent was removed by evaporation, and the product was purified by
column chromatography with 15% ethyl acetate in hexanes and 30%
ethyl acetate in hexanes to give
N-(4-isopropylphenyl)-2-[3-(2-methox-
y-5-nitrophenyl)-thioureido]-2-phenyl acetamide (18.8 mg, yield
79.2%)
[0278] Experiment 20:
[0279] C20 tert-butyl
[1-(4-trifluoromethylphenylcarbamoyl)-1-phenyl-methy- l]-carbamate
87
[0280] tert-butyl
[1-(4-trifluoromethylphenylcarbamoyl)-1-phenyl-methyl]-c- arbamate
(708 mg, 96.5%); from [(tert-butoxycarbonyl)amino](phenyl)acetic
acid (500 mg, 2 mmoles) reacted with isobutyl chloroformate (235
.mu.l, 2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles)
in THF (5 ml) at -40.about.-50.degree. C., followed by being
queched with 4-trifluoromethylaniline (386 mg, 2.4 mmoles).
[0281] D20 2-Amino-N-(4-trifluoromethyphenyl)-2-phenylacetamide
88
[0282] 2-Amino-N-(4-trifluoromethylphenyl)-2-phenylacetamide (375
mg, quantitative); from tert-butyl
[1-(4-trifluoromethylphenylcarbamoyl)-1-ph- enyl-methyl]-carbamate
(500 mg, 1.27 mmoles) reacted with formic acid (5 ml) at 60.degree.
C. for 0.5 hour.
[0283] E20.1
N-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-th-
ioureido]-2-phenyl acetamide 89
[0284]
N-(4-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide(19.2 mg, 76.2%); from
2-Amino-N-(4-trifluoromethyph- enyl)-2-phenylacetamide (14.7 0.05
mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate (12.6
mg, 0.06 mmoles) and triethylamine (15.2 mg, 0.15 mmoles) in
dichloromethane (1 ml) at ambient temperature overnight.
[0285] E20.2
2-[3-(2-chloro-5-nitrophenyl)-thioureido]-N-(4-trifluoromethy-
lphenyl)-2-phenyl acetamide 90
[0286]
2-[3-(2-chloro-5-nitrophenyl)-thioureido]-N-(4-trifluoromethylpheny-
l)-2-phenyl acetamide (12.5 mg, 74%); from
2-Amino-N-(4-trifluoromethylphe- nyl)-2-phenylacetamide (13.1 mg,
0.0332 mmoles) reacted with 2-chloro-5-nitrophenylisothiocyanate
(9.7 mg, 0.045 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0287] E20.3
2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-N-(4-trifluoromet-
hylphenyl)-2-phenyl acetamide 91
[0288]
2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-N-(4-trifluoromethylphe-
nyl)-2-phenyl acetamide (13.5 mg, 82.3%); from
2-Amino-N-(4-trifluoromethy- lphenyl)-2-phenylacetamide (13.1 mg,
0.0332 mmoles) reacted with 5-chloro-2-methoxyphenylthioisocyanate
(9.0 mg, 0.045 mmoles) in dichloromethane (1 ml) 15 at 60.degree.
C. overnight.
[0289] E20.4
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-trifluoromethylp-
henyl)-2-phenyl acetamide 92
[0290]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-trifluoromethylphenyl)-
-2-phenyl acetamide (16.1 mg, 64.6%); from
2-Amino-N-(4-trifluoromethylphe- nyl)-2-phenylacetamide (15 mg,
0.051 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (15
mg, 0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0291] Experiment 21:
[0292] E21.1
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(3-trifluorometh-
ylphenyl)-2-phenyl acetamide 93
[0293]
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(3-trifluoromethylphen-
yl)-2-phenyl acetamide (23.5 mg, 90.5%); from
2-Amino-N-(3-trifluoromethyl- phenyl)-2-phenylacetamide (15 mg,
0.051 mmoles) reacted with 2-chloro-5-nitrophenylisothiocyanate (15
mg, 0.07 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0294] Experiment 22:
[0295] C22 tert-butyl
[1-(8-quinolinylcarbamoyl)-1-phenyl-methyl]-carbamat- e 94
[0296] tert-butyl
[1-(8-quinolinylcarbamoyl)-1-phenyl-methyl]-carbamate (1.696 g);
was made from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (1.0
g, 3.98 mmoles) reacted with isobutyl chloroformate (569.4,.mu.l,
4.38 mmoles) and N-methylmorpholine (482.2 .mu.l, 4.38 mmoles) in
THF (10 ml) at -40.about.-50.degree. C., followed by being queched
with 8-aminoquinoline (689.2 mg, 4.78 mmoles).
[0297] D22 2-Amino-N-(8-quinolinyl)-2-phenylacetamide formic acid
salt 95
[0298] 2-Amino-N-(8-quinolinyl)-2-phenylacetamide formic acid salt
(0.915 g, quantitative); from tert-butyl
[1-(8-quinolinylcarbamoyl)-1-phenyl-met- hyl]-carbamate (1.1 g, 2.9
mmoles) reacted with formic acid (20 ml) at 60.degree. C. for 0.5
hour.
[0299] E22.1
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(8-quinolinyl)-2-ph- enyl
acetamide 96
[0300]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(8-quinolinyl)-2-phenyl
acetamide (17 mg, 66.7%); from
2-Amino-N-(8-quinolinyl)-2-phenylacetamide (15 mg, 0.054 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0301] E22.2
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(8-quinolinyl)--
2-phenyl acetamide 97
[0302]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(8-quinolinyl)-2-phen-
yl acetamide (14.6 mg, 83.2%); from
2-Amino-N-(8-quinolinyl)-2-phenylaceta- mide (10 mg, 0.036 mmoles)
reacted with 2-methoxy-5-nitrophenylisothiocyan- ate (10 mg, 0.0476
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0303] E22.3
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(6-quinolinyl)-2-ph- enyl
acetamide 98
[0304]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(8-quinolinyl)-2-phenyl
acetamide (17 mg, quantitative); from
2-Amino-N-(8-quinolinyl)-2-phenylac- etamide (10 mg, 0.036 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyana- te (9 mg, 0.046
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0305] Experiment 23:
[0306] C23 tert-butyl
[1-(4-methyl-3-trifluoromethylphenylcarbamoyl)-1-phe-
nyl-methyl]-carbamate 99
[0307] tert-butyl
[1-(4-methyl-3-trifluoromethylphenylcarbamoyl)-1-phenyl--
methyl]-carbamate (762 mg, 93.7%); from
[(tert-butoxycarbonyl)amino](pheny- l)acetic acid (500 mg, 2
mmoles) reacted with isobutyl chloroformate (235,.mu.l, 2.2 mmoles)
and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5 ml) at
-40.about.-50.degree. C., followed by being queched with
4-methy-3-trifluoromethylaniline (420.4 mg, 2.4 mmoles).
[0308] D23
2-Amino-N-(4-methyl-3-trifluoromethyphenyl)-2-phenylacetamide
100
[0309]
2-Amino-N-(4-methyl-3-trifluoromethyphenyl)-2-phenylacetamide
(409.7 mg, 71.4%); from tert-butyl
[1-(4-methyl-3-trifluoromethylphenylca-
rbamoyl)-1-phenyl-methyl]-carbamate (760 mg, 1.86 mmoles) reacted
with formic acid (4 ml) at 60.degree. C. for 0.5 hour.
[0310] E23.1
N-(4-methyl-3-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrop-
henyl)-thioureido]-2-phenyl acetamide 101
[0311]
N-(4-methyl-3-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-
-thioureido]-2-phenyl acetamide(8.0 mg, 48.2%); from
2-Amino-N-(4-methyl-3-trifluoromethyphenyl)-2-phenylacetamide (10
mg, 0.032 mmoles) reacted with
2-methoxy-5-nitrophenylisothiocyanate (9.0 mg, 0.043 mmoles) in
dichloromethane (1 ml) at ambient temperature overnight.
[0312] E23.2
N-(4-methyl-3-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrop-
henyl)-ureido]-2-phenyl acetamide 102
[0313]
N-(4-methyl-3-trifluoromethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-
-ureido]-2-phenyl acetamide (14.2 mg, 88.3%); from
2-Amino-N-(4-methyl-3-t- rifluoromethyphenyl)-2-phenylacetamide (10
mg, 0.032 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate
(9.0 mg, 0.046 mmoles) in dichloromethane (1 ml) 60.degree. C.
overnight.
[0314] Experiment 24:
[0315] C24 tert-butyl [1-(3-dim
thylamino-phenylcarbamoyl)-1-phenyl-methyl- ]-carbamate 103
[0316] tert-butyl
[1-(3-dimethylamino-phenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
(241 mg, 32.8%); from [(tert-butoxycarbonyl)amino](phenyl)acetic
acid (500 mg, 2 mmoles) reacted with isobutyl chloroformate (235
.mu.l, 2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2,2 mmoles)
in THF (5 ml) at -40.about.-50.degree. C., followed by being
queched with 3-dimethylaminoaniline hydrochloride (501.88 mg, 2.4
mmoles).
[0317] D24 2-Amino-N-(3-N,N-dimethylaminophenyl)-2-phenylacetamide
104
[0318] 2-Amino-N-(3-N,N-dimethylaminophenyl)-2-phenylacetamide
(25.4 mg, 14.1%); from tert-butyl
[1-(3-dimethylamino-phenylcarbamoyl)-1-phenyl-met- hyl]-carbamate
(247 mg, 0.669 mmoles) reacted with formic acid (1.5 ml) at
60.degree. C. for 0.5 hour.
[0319] E24.1
N-(3-N,N-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiou-
reido]-2-phenyl acetamide 105
[0320]
N-(3-N,N-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-
-2-phenyl acetamide (11.8 mg, 82%); from
2-Amino-N-(4-methyl-3-trifluorome- thyphenyl)-2-phenylacetamide
(8.2 mg, 0.042 mmoles) reacted with
2-methoxy-5-nitrophenylisothiocyanate (9.0 mg, 0.043 mmoles) in
dichloromethane (1 ml) at 60.degree. C. overnight.
[0321] E24.2
N-(3-N,N-dimethylphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-ureid-
o]-2-phenyl acetamide 106
[0322] N-(3-N,N-dimethyl
phenyl)-2-[3-(2-methoxy-5-nitrophenyl)-ureido]-2-- phenyl acetamide
(9.3 mg, 66.2%); from 2-Amino-N-(4-methyl-3-trifluorometh-
yphenyl)-2-phenylacetamide (8.2 mg, 0.042 mmoles) reacted with
2-methoxy-5-nitrophenylisocyanate (9.0 mg, 0.046 mmoles) in
dichloromethane (1 ml) 60.degree. C. overnight.
[0323] Experiment 25:
[0324] C25 tert-butyl
[1-(6-quinolinylcarbamoyl)-1-phenyl-methyl]-carbamat- e 107
[0325] tert-butyl
[1-(6-quinolinylcarbamoyl)-1-phenyl-methyl]-carbamate (177 mg,
24.6%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (500
mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2
mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5
ml) at -40.about.-50.degree. C., followed by being queched with
6-aminoquinoline (346 mg, 2.4 mmoles).
[0326] D25 2-Amino-N-(6-quinolinyl)-2-phenylacetamide 108
[0327] 2-Amino-N-(6-quinolinyl)-2-phenylacetamide (62 mg, 47.6);
from tert-butyl
[1-(6-quinolinylcarbamoyl)-1-phenyl-methyl]-carbamate (177 mg,
0.469 mmoles) reacted with formic acid (1 ml) at 60.degree. C. for
0.5 hour.
[0328] E25.1
N-(quinolin-6-yl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 109
[0329]
N-(quinolin-6-yl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-phen-
yl acetamide (13.3 mg, 75.5%); from
2-Amino-N-(quinolin-6-yl)-2-phenylacet- amide (10 mg, 0.036 mmoles)
reacted with 2-methoxy-5-nitrophenylisothiocya- nate (9.0 mg, 0.043
mmoles) in dichloromethane (1 ml) at 60.degree. C. overnight.
[0330] Experiment 26:
[0331] C26 tert-butyl
[1-(4-nitrophenylcarbamoyl)-1-phenyl-methyl]-carbama- te 110
[0332] tert-butyl
[1-(4-nitrophenylcarbamoyl)-1-phenyl-methyl]-carbamate (280 mg,
37.8%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (500
mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2
mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5
ml) at -40.about.-50.degree. C., followed by being queched with
4-nitroaniline (331,2 mg, 2.4 mmoles).
[0333] D26 2-Amino-N-(4-nitrophenyl)-2-phenylacetamide 111
[0334] 2-Amino-N-(4-nitrophenyl)-2-phenylacetamide (114.5 mg,
55.9%); from tert-butyl
[1-(4-nitrophenylcarbamoyl)-1-phenyl-methyl]-carbamate (280 mg,
0.754 mmoles) reacted with formic acid (2 ml) at 60.degree. C. for
0.5 hour.
[0335] E26.1
N-(4-nitrophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 112
[0336]
N-(4-nitrophenyl)-2-[3-(2-methox-5-nitrophenyl)-thioureido]-2-pheny-
l acetamide (23.4 mg, 91%); from
2-Amino-N-(4-nitrophenyl)-2-phenylacetami- de (14.5 mg, 0.0535
mmoles) reacted with 2-methoxy-5-nitrophenylisothiocya- nate (12.6
mg, 0.06 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0337] E26.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-nitrophenyl)-2-p-
henyl acetamide 113
[0338]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-nitrophenyl)-2-phenyl
acetamide (25 mg, 97.6%); from
2-Amino-N-(4-nitrophenyl)-2-phenylacetamid- e (15 mg, 0.055 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0339] Experiment 27:
[0340] C27 tert-butyl
[1-(4-trifluoromethoxyphenylcarbamoyl)-1-phenyl-meth- yl]-carbamate
114
[0341] tert-butyl
[1-(4-trifluoromethoxyphenylcarbamoyl)-1-phenyl-methyl]-- carbamate
(302 mg, 36.9%); from [(tert-butoxycarbonyl)amino](phenyl)acetic
acid (500 mg, 2 mmoles) reacted with isobutyl chloroformate (235
.mu.l, 2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2,2 mmoles)
in THF (5 ml) at -40.about.-50.degree. C., followed by being
queched with 4-trifluoromethoxyaniline (424.8 mg, 2.4 mmoles).
[0342] D27 2-Amino-N-(4-trifluoromethylphenyl)-2-phenylacetamide
formic acid salt 115
[0343] 2-Amino-N-(4-trifluoromethyl phenyl)-2-phenylacetamide
formic acid salt (221.5 mg, 91.1%); from tert-butyl
[1-(4-trifluoromethoxyphenylcarba- moyl)-1-phenyl-methyl]-carbamate
(280 mg, 0.682 mmoles) reacted with formic acid (2 ml) at
60.degree. C. for 0.5 hour.
[0344] E27.1
N-(4-trifluoromethoxyphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-t-
hioureido]-2-phenyl acetamide 116
[0345]
N-4-trifluoromethoxyphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thiourei-
do]-2-phenyl acetamide (11.8 mg, 59.4%); from
2-Amino-N-(4-trifluoromethox- yyphenyl)-2-phenylacetamide (13.6 mg,
0.038 mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate
(12.6 mg, 0.06 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0346] E27.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-trifluoromethxyp-
henyl)-2-phenyl acetamide 117
[0347]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-trifluoromethxyphenyl)-
-2-phenyl acetamide (20.7 mg, 62.9%); from
2-Amino-N-(4-trifluoromethoxphe- nyl)-2-phenylacetamide (15 mg,
0.048 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (15
mg, 0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0348] Experiment 28:
[0349] C28 tert-butyl [1-(4-methoxy
phenylcarbamoyl)-1-phenyl-methyl]-carb- amate 118
[0350] tert-butyl
[1-(4-methoxyphenylcarbamoyl)-1-phenyl-methyl]-carbamate (546 mg,
76.9%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (500
mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2
mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5
ml) at -40.about.-50.degree. C., followed by being queched with
p-anisidine (295.6 mg, 2.4 mmoles).
[0351] D28 2-Amino-N-(4-methoxyphenyl)-2-phenylacetamide 119
[0352] 2-Amino-N-(4-methylphenyl)-2-phenylacetamide (313 mg, 87%);
from tert-butyl
[1-(4-methoxyphenylcarbamoyl)-1-phenyl-methyl]-carbamate (500 mg,
1.4 mmoles) reacted with formic acid (4 ml) at 60.degree. C. for
0.5 hour.
[0353] E28.1
N-(4-methoxyphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido-
]-2-phenyl acetamide 120
[0354]
N-(4-methoxyphenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-ph-
enyl acetamide (24.5 mg, 91%); from
2-Amino-N-(4-methoxyphenyl)-2-phenylac- etamide (14.8 mg, 0.0578
mmoles) reacted with 2-methoxy-5-nitrophenylisoth- iocyanate (12.6
mg, 0.06 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0355] E28.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methoxyphenyl)-2-
-phenyl acetamide 121
[0356]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-methoxyphenyl)-2-pheny-
l acetamide (24.7 mg, 92.9%); from
2-Amino-N-(4-methoxyphenyl)-2-phenylace- tamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenylisocyanat- e (15 mg,
0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0357] Experiment 29:
[0358] C29 tert-butyl [1-(indan-5-yl
carbamoyl)-1-phenyl-methyl]-carbamate 122
[0359] tert-butyl [1-(indan-5-yl
carbamoyl)-1-phenyl-methyl]-carbamate (586 mg, 80.3%); from
[(tert-butoxycarbonyl)amino](phenyl)acetic acid (500 mg, 2 mmoles)
reacted with isobutyl chloroformate (235 .mu.l, 2.2 mmoles) and
N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5 ml) at
-40.about.-50.degree. C., followed by being quenched with
5-aminoindane (424.8 mg, 2.4 mmoles).
[0360] D29 2-Amino-N-(indan-5-yl)-2-phenylacetamide 123
[0361] 2-Amino-N-(indan-5-yl)-2-phenylacetamide (230 mg, 63.3%);
tert-butyl [1-(indan-5-ylcarbamoyl)-1-phenyl-methyl]-carbamate
(500mg, 1.364 mmoles) reacted with formic acid (4 ml) at 60.degree.
C. for 0.5 hour.
[0362] E29.1
N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-p-
henyl acetamide 124
[0363]
N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]-2-phenyl
acetamide (22.4 mg, 84.5%); from
2-Amino-N-(indan-5-yl)-2-phenylacetamide (13.9 mg, 0.0556 mmoles)
reacted with 2-methoxy-5-nitrophenylisothiocyana- te (12.6 mg, 0.06
mmoles) in dichloromethane (1 ml) at 60.degree. C. overnight.
[0364] E29.2
N-(indan-5-yl)-2-[3-(2-chloro-5-nitrophenyl)-thioureido]-2-ph- enyl
acetamide 125
[0365]
N-(indan-5-yl)-2-[3-(2-chloro-5-nitrophenyl)-thioureido]-2-phenyl
acetamide (26.1 mg, 96.9%); from
2-Amino-N-(indan-5-yl)-2-phenylacetamide (15 mg, 0.056 mmoles)
reacted with 2-chloro-5-nitrophenylthioisocyanate (15 mg, 0.07
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0366] E29.3
N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-ureido]-2-pheny- l
acetamide 126
[0367]
N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-ureido]-2-phenyl
acetamide (21 mg, 81.4%); from
2-Amino-N-(indan-5-yl)-2-phenylacetamide (15 mg, 0.056 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0368] C29* R-tert-butyl
[1-(indan-5-yl-carbamoyl)-1-phenyl-methyl]-carbam- ate 127
[0369] R-tert-butyl [1-(indan-5-yl
carbamoyl)-1-phenyl-methyl]-carbamate (584.1 mg); from
[(R-tert-butoxycarbonyl)amino](phenyl)acetic acid (600 mg, 2.39
mmoles) reacted with isobutyl chloroformate (339 .mu.l, 2.62
mmoles) and N-methylmorpholine(288 .mu.l, 2.62 mmoles) in THF (2
ml) at -78.degree. C., followed by being quenched with
5-aminoindan(401 mg, 2.99 mmoles).
[0370] D29* R-2-Amino-N-(indan-5-yl)-2-phenylacetamide 128
[0371] R-2-Amino-N-(indan-5-yl)-2-phenylacetamide (484.6 mg,);
R-tert-butyl [1-(indan-5-ylcarbamoyl)-1-phenyl-methyl]-carbamate
(584.1 mg) reacted with formic acid (2 ml) at 55.degree. C. for 25
min.
[0372] E29.1*
R-N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-ureido]-2-ph- enyl
acetamide 129
[0373]
R-N-(indan-5-yl)-2-[3-(2-methoxy-5-nitrophenyl)-ureido]-2-phenyl
acetamide (670.0 mg, 79.9%); from
2-Amino-N-(indan-5-yl)-2-phenylacetamid- e (484.6 mg, 1.8194
mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (459 mg,
2.365 mmoles) in dichloromethane (12 ml) at 60.degree. C. for 2
hours.
[0374] Experiment 30:
[0375] C3 tert-butyl
[1-(2-naphthylcarbamoyl)-1-phenyl-methyl]-carbamate 130
[0376] tert-butyl
[1-(2-naphthylcarbamoyl)-1-phenyl-methyl]-carbamate (689 mg,
91.9%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (500
mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2
mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5
ml) at -40.about.-50.degree. C., followed by being quenched with
2-aminonaphthalene (345.12 mg, 2.4 mmoles).
[0377] D30 2-Amino-N-(2-naphthyl)-2-phenylacetamide 131
[0378] 2-Amino-N-(2-naphthyl)-2-phenylacetamide (411 mg, 93.3%);
from tert-butyl [1-(2-naphthylcarbamoyl)-1-phenyl-methyl]-carbamate
(600 mg, 1.594 mmoles) reacted with formic acid (6 ml) at
60.degree. C. for 0.5 hour.
[0379] E30.1
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(2-naphthyl)-2--
phenyl acetamide 132
[0380]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(2-naphthyl)-2-phenyl
acetamide (23.5 mg, 89.4%); from
2-Amino-N-(2-naphthyl)-2-phenylacetamide (15 mg, 0.054 mmoles)
reacted with 2-methoxy-5-nitrophenylisothiocyanate (15 mg, 0.0714
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0381] E30.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(2-naphthyl)-2-phen- yl
acetamide 133
[0382] 2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-
N-(2-naphthyl)-2-phenyl acetamide (16.5 mg, 64.9%); from
2-Amino-N-(2-naphthyl)-2-phenylacetamide (15 mg, 0.054 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0383] Experiment 31:
[0384] C31 tert-butyl
[1-(3-trifluoromethylphenylcarbamoyl)-1-phenyl-methy- l]-carbamate
134
[0385] tert-butyl
[1-(3-trifluoromethylphenylcarbamoyl)-1-phenyl-methyl]-c- arbamate
(708 mg, 90.2%); from [(tert-butoxycarbonyl)amino](phenyl)acetic
acid (500 mg, 2 mmoles) reacted with isobutyl chloroformate (235
.mu.l, 2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles)
in THF (5 ml) at -40.about.-50.degree. C., followed by being
queched with 3-trifluoromethylaniline (386.4 mg, 2.4 mmoles).
[0386] D37 2-Amino-N-(3-trifluoromethylphenyl)-2-phenylacetamide
135
[0387] 2-Amino-N-(3-trifluoromethylphenyl)-2-phenylacetamide (313
mg, 92%); from tert-butyl
[1-(3-trifluoromethylphenylcarbamoyl)-1-phenyl-meth- yl]-carbamate
(600 mg, 1.52 mmoles) reacted with formic acid (6 ml) at 60.degree.
C. for 0.5 hour.
[0388] D37*
(R)-2-Amino-N-(3-trifluoromethylphenyl)-2-phenylacetamide 136
[0389] (R)-(-)-2-phenylglycine chloride hydrochloride (2.0 g, 0.97
mmoles) was mixed with tetrahydrofuran(10 ml) at -60.degree. C.,
then 3-trifluoromethylaniline (3.374 g, 2.13 mmoles) was added.
After being stirred for 1 hour, the reaction mixture was diluted
with dichloromethane and washed by 1 M sodium hydroxide. The
organic layer was dried with sodium sulfate, concentrated,
triturated with hexanes to give
(R)-2-Amino-N-(3-trifluoromethylphenyl)-2-phenylacetamide (2.3 g,
yield: 80.5%)
[0390] E31.1
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3-trifluoromet-
hylphenyl)-2-phenyl acetamide 137
[0391] 2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-
N-(3-trifluoromethylphenyl)-2-phenyl acetamide (20.5 mg, 79.6%);
from 2-Amino-N-(3-trifluoromethylphenyl)-2-phenylacetamide (15 mg,
0.051 mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate
(15 mg, 0.0714 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0392] E31.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3-trifluoromethylp-
henyl)-2-phenyl acetamide 138
[0393]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3-trifluoromethylphenyl)-
-2-phenyl acetamide (25 mg, quantitative); from
2-Amino-N-(3-trifuromethyl- phenyl)-2-phenylacetamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg,
0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0394] Experiment 32:
[0395] C32 tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
139
[0396] tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate (666
mg, 94.4%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid
(500 mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l,
2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF
(5 ml) at -40.about.-50.degree. C., followed by being quenched with
3,4-dinethylaniline (290.18 mg, 2.4 mmoles).
[0397] D32 2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide 140
[0398] 2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide (416 mg,
96.6%); from tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbama- te (600
mg, 1.93 mmoles) reacted with formic acid (6 ml) at 60.degree. C.
for 0.5 hour.
[0399] E32.1
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylphe-
nyl)-2-phenyl acetamide 141
[0400] 2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-
N-(3,4-dimethylphenyl)-- 2-phenyl acetamide (19.1 mg, 69%); from
2-Amino-N-(3,4-dimethylphenyl)-2-p- henylacetamide (15 mg, 0.059
mmoles) reacted with 2-chloro-5-nitrophenylis- othiocyanate (15 mg,
0.07 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0401] E32.2
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylph-
enyl)-2-phenyl acetamide 142
[0402]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dimethylphenyl)--
2-phenyl acetamide (19.5 mg, 71.1%); from
2-Amino-N-(3,4-dimethylphenyl)-2- -phenylacetamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate (15 mg,
0.0714 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0403] E32.3
2-[3-(2-fluoro-5-nitro-phenyl)-ureido]-N-(3,4-dimethylphenyl)-
-2-phenyl acetamide 143
[0404]
2-[3-(2-fluoro-5-nitro-phenyl)-ureido]-N-(3,4-dimethylphenyl)-2-phe-
nyl acetamide (13.4 mg, 87%); from
2-Amino-N-(3,4-dimethylphenyl)-2-phenyl- acetamide (9 mg, 0.0354
mmoles) reacted with 2-fluoro-5-nitrophenylisocyan- ate (9 mg,
0.0494 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0405] E32.4 2-[3-(
2-methoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylpheny- l)-2-phenyl
acetamide 144
[0406]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylphenyl)-2-ph-
enyl acetamide (22.1 mg, 83.5%); from
2-Amino-N-(3,4-dimethylphenyl)-2-phe- nylacetamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenyliso- cyanate (15 mg,
0.077 mmoles) in dichloromethane (8 ml) at 60.degree. C.
overnight.
[0407] E32.5
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylph-
enyl)-2-phenyl acetamide 145
[0408]
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylphenyl)--
2-phenyl acetamide (129 mg, 83.5%); from
(R)-2-Amino-N-(3,4-dimethylphenyl- )-2-phenylacetamide (84 mg,
0.237 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (110
mg, 0.567 mmoles) in dichloromethane (5 ml) at 60.degree. C.
overnight.
[0409] E32.6
2-[3-(2-(N,N-dimethylaminoethoxy-5-nitro-phenyl)-ureido]-N-3,-
4-dimethylphenyl)-2-phenyl acetamide 146
[0410] 2-(N,N-dimethylaminoethoxy)-5-nitroaniline (25 mg, 0.11
mmoles) was mixed with triphosgene (32 mg) in dichloromethane at
ambient temperature for 0.5 hour. Then
2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide (40 mg, 0.157
mmoles) was added and heated to 60.degree. C. for 1 hour. The
product was diluted with dichloromethane and purified by column
chromatography with 1.5% methanol (2MNH.sub.3) in dichloromethane
to give
2-[3-(2-(N,N-dimethylaminoethoxy-5-nitro-phenyl)-ureido]-N-(3,4-dimethylp-
henyl)-2-phenyl acetamide (3.2 mg, 5.7%)
[0411] E32.7
2-[3-(2-methoxy-5-nitro-phenyl)-cyano-quanadine]-N-(3,4-dimet-
hylphenyl)-2-phenyl acetamide 147
[0412]
2-[3-(2-methoxy-5-nitro-phenyl)-cyano-guanadine]-N-(3,4-dimethylphe-
nyl)-2-phenyl acetamide (21.2 mg, 11%) was isolated as a white
solid. The title compound was made by reaction of Sodium t-butoxide
(0.492 mmol) with a solution of Cyanamide (20 mg, 0.492 mmol) in
DMF (3 ml) at room temperature for 20 min followed by the addition
of 2-methoxy-5-nitrophenylisothiocyanate (50 mg, 0.492 mmol). The
solution was then cooled to 0.degree. C. and triethylamine (0.096
ml, 0.688 mmol) was added. Next the starting material
2-Amino-N-(3,4-dimethylphenyl)-2-ph- enylacetamide (100 mg, 0.393
mmol) was added and finally HgCl.sub.2 (112.4 mg, 0.443 mmol). The
reaction mixture was stirred at 0.degree. C. for 2 hours. The final
product was isolated from the reaction mixture by dilution in
ethylacetate followed by washing with water and then with brine.
The organic extracts were dried over Na.sub.2SO.sub.4 and
concentrated to dryness. The product was purified by flash
chromatography on Silica gel with a gradient elution of 10% to 40%
Ethylacetate in Hexane.
[0413] Experiment 33:
[0414] C33* (R)-tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-methy- l]-carbamate
148
[0415] (R)-tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate (613
mg, 86.9%); from (R)-[(tert-butoxycarbonyl)amino](phenyl)acet- ic
acid (500 mg, 2 mmoles) reacted with isobutyl chloroformate (235
.mu.l, 2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles)
in THF (5 ml) at -78.degree. C., followed by being quenched with
3,4-dimethylaniline (290.18 mg, 2.4 mmoles).
[0416] D33* (R)-2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide
149
[0417] (R)-2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide (84 mg,
97.4%); from (R)-tert-butyl
[1-(3,4-dimethylphenylcarbamoyl)-1-phenyl-met- hyl]-carbamate (120
mg, 0.039 mmoles) reacted with formic acid (0.5 ml) at 60.degree.
C. for 0.5 hour.
[0418] E33.1 *
(R)-2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,4-dime-
thylphenyl)-2-phenyl acetamide 150
[0419] (R)-2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-
N-(3,4-dimethylphenyl)-2-phenyl acetamide (456 mg, 83%); from
(R)-2-Amino-N-(3,4-dimethylphenyl)-2-phenylacetamide (300 mg, 1.18
mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate (300 mg,
1.43 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight
[0420] Experiment 34:
[0421] C34 tert-butyl
[1-(3,5-dimethylphenylcarbamoyl)-1-phenyl-methyl]-ca- rbamate
151
[0422] tert-butyl
[1-(3,5-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbam- ate (620
mg, 87.8%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid
(500 mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l,
2.2 mmoles) and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF
(5 ml) at -40.about.-50.degree. C., followed by being queched with
3,5-dimethylaniline (290.8 mg, 2.4 mmoles).
[0423] D34 2-Amino-N-(3,5-dimethylphenyl)-2-phenylacetamide 152
[0424] 2-Amino-N-(3,5-dimethylphenyl)-2-phenylacetamide (365 mg,
83.5%); from tert-butyl
[1-(3,5-dimethylphenylcarbamoyl)-1-phenyl-methyl]-carbama- te (609
mg, 1.718 mmoles) reacted with formic acid (5 ml) at 60.degree. C.
for 0.5 hour.
[0425] E34.1
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylphe-
nyl)-2-phenyl acetamide 153
[0426]
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylphenyl)-2-
-phenyl acetamide (24.3 mg, 87.8%); from
2-Amino-N-(3,5-dimethyphenyl)-2-p- henylacetamide (15 mg, 0.059
mmoles) reacted with 2-chloro-5-nitrophenylis- othiocyanate (15 mg,
0.07 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0427] E34.2
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylph-
enyl)-2-phenyl acetamide 154
[0428]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylphenyl)--
2-phenyl acetamide (27.4 mg, quantitative); from
2-Amino-N-(3,5-dimethylph- enyl)-2-phenylacetamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate (15 mg,
0.0714 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0429] E34.3
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,5-dimethylphenyl-
)-2-phenyl acetamide 155
[0430]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,5-dimethylphenyl)-2-ph-
enyl acetamide (25.6 mg, 96.7%); from
2-Amino-N-(3,5-dimethylphenyl)-2-phe- nylacetamide (15 mg, 0.059
mmoles) reacted with 2-methoxy-5-nitrophenyliso- cyanate (15 mg,
0.077 mmoles) in dichloromethane (0.8 ml) at 60.degree. C.
overnight.
[0431] Experiment 35:
[0432] C35 tert-butyl
[1-(4-vinylphenylcarbamoyl)-1-phenyl-methyl]-carbama- te 156
[0433] tert-butyl
[1-(4-vinylphenylcarbamoyl)-1-phenyl-methyl]-carbamate (610 mg,
86.4%); from [(tert-butoxycarbonyl)amino](phenyl)acetic acid (500
mg, 2 mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2
mmoles) and N-methylmorpholine(241 .mu.l, 2.2 mmoles) in THF (5 ml)
at -40.about.-50.degree. C., followed by being quenched with
4-vinylaniline (290.8 mg, 2.4 mmoles).
[0434] D35 2-Amino-N-(4-vinylphenyl)-2-phenylacetamide 157
[0435] 2-Amino-N-(4-vinylphenyl)-2-phenylacetamide (188 mg, 44.7%);
from tert-butyl [1
-(4-vinylphenylcarbamoyl)-1-phenyl-methyl]-carbamate (587 mg, 1.66
mmoles) reacted with formic acid (5 ml) at 60.degree. C. for 0.5
hour.
[0436] E35.1
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(4-vinylphenyl)--
2-phenyl acetamide 158
[0437]
2-[3-(2-chloro-5-nitro-phenyl)-thioureido]-N-(4-vinylphenyl)-2-phen-
yl acetamide (15.2 mg, 55.1%); from
2-Amino-N-(4-vinylphenyl)-2-phenylacet- amide (15 mg, 0.059 mmoles)
reacted with 2-chloro-5-nitrophenylisothiocyan- ate (15 mg, 0.07
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0438] E35.2
2-[3-(2-methyoxy-5-nitro-phenyl)-thioureido]-N-(4-vinylphenyl-
)-2-phenyl acetamide 159
[0439]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(4-vinylphenyl)-2-phe-
nyl acetamide (21.7 mg, 79.5%); from
2-Amino-N-(4-vinylphenyl)-2-phenylace- tamide (15 mg, 0.059 mmoles)
reacted with 2-methoxy-5-nitrophenylisothiocy- anate (15 mg, 0.0714
mmoles) in dichloromethane (0.5 ml) at 60.degree. C. overnight.
[0440] E35.3
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-vinylphenyl)-2-p-
henyl acetamide 160
[0441]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-vinylphenyl)-2-phenyl
acetamide (22.6 mg, 85.4%); from
2-Amino-N-(4-vinylphenyl)-2-phenylacetam- ide (15 mg, 0.059 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0442] Experiment 36:
[0443] C36 tert-butyl-[1-(6-m
thylpyridin-3-ylcarbamoyl)-1-phenyl-methylca- rbamate 161
[0444]
tert-butyl-[1-(6-methylpyridin-3-ylcarbamoyl)-1-phenyl-methylcarbam-
ate (235 mg, 74.4%); from
[(tert-butoxycarbonyl)amino](phenyl)acetic acid (279 mg, 1.11
mmoles) reacted with isobutyl chloroformate (130 .mu.l, 1.22
mmoles) and N-methylmorpholine (133 .mu.l, 1.22 mmoles) in THF (2.5
ml) at -40.about.-50.degree. C., followed by being queched
3-amino-6-methylpyridine (100 mg, 0.925 mmoles).
[0445] D36 2-Amino-N-(6-methylpyridin-3-yl)-2-phenylacetamide
162
[0446] 2-Amino-N-(6-methylpyridin-3-yl)-2-phenylacetamide (87.3 mg,
52.9%); from
tert-butyl-[1-(6-methylpyridin-3-ylcarbamoyl)-1-phenyl-methy-
lcarbamate (235 mg, 0.688 mmoles) reacted with formic acid (2.5 ml)
at 60.degree. C. for 0.5 hour.
[0447] E36.1
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(6-methylpyridin-3--
yl)-2-phenyl acetamide 163
[0448]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(6-methylpyridin-3-yl)-2--
phenyl acetamide (17.5 mg, 98.2%); from
2-Amino-N-(6-methylpyridin-3-yl)-2- -93 phenylacetamide (10 mg,
0.041 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate (10
mg, 0.052 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0449] Experiment 37
[0450] C37
tert-butyl-[1-(6-trifluoromethylpyridin-3-ylcarbamoyl)-1-phenyl-
-methylcarbamate 164
[0451]
tert-butyl-[1-(6-trifluoromethylpyridin-3-ylcarbamoyl)-1-phenyl-met-
hylcarbamate (477 mg, 55.8%); from
[(tert-butoxycarbonyl)amino](phenyl)ace- tic acid (500 mg, 2
mmoles) reacted with isobutyl chloroformate (235 .mu.l, 2.2 mmoles)
and N-methylmorpholine (241 .mu.l, 2.2 mmoles) in THF (5 ml) at
-40.about.-50.degree. C., followed by being quenched
3-amino-6-trifluoromethylpyridine (350 mg, 2.16 mmoles).
[0452] D37
2-Amino-N-(6-trifluoromethylpyridin-3-yl)-2-phenylacetamide 165
[0453] 2-Amino-N-(6-trifluoromethylpyridin-3-yl)-2-phenylacetamide
(317 mg, 89%); from
tert-butyl-[1-(6-trifluoromethylpyridin-3-ylcarbamoyl)-1-p-
henyl-methylcarbamate (477 mg, 1.397 mmoles) reacted with formic
acid (5 ml) at 60.degree. C. for 0.5 hour.
[0454] E37.1
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(6-trifluoromethylp-
yridin-3-yl)-2-phenyl acetamide 166
[0455]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(6-trifluoromethylpyridin-
-3-yl)-2-phenyl acetamide (16.3 mg, 97.9%); from
2-Amino-N-(6-trifluoromet- hylpyridin-3-yl)-2-phenylacetamide (10
mg, 0.034 mmoles) reacted with 2-methoxy-5-nitrophenylisocyanate
(10 mg, 0.052 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0456] E37.2
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(6-trifluoromet-
hylpyridin-3-yl)-2-phenyl acetamide 167
[0457]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(6-trifluoromethylpyr-
idin-3-yl)-2-phenyl acetamide (12.6 mg, 73.3%); from
2-Amino-N-(6-trifluoromethylpyridin-3-yl)-2-phenylacetamide (10 mg,
0.034 mmoles) reacted with 2-methoxy-5-nitrophenylisothiocyanate
(10 mg, 0.048 mmoles) in dichloromethane (0.5 ml) at 60.degree. C.
overnight.
[0458] Experiment 38:
[0459] E38.1
N-(4-bromophenyl)-2-[3-(2-methoxy-5-nitrophenyl)-thioureido]--
2-phenyl acetamide 168
[0460] N-(4-bromophenyl)-2-[3-(2-nitrophenyl)-thioureido]-2-phenyl
acetamide (23.5 mg, 95.9%); from
2-Amino-N-(4-bromoyphenyl)-2-phenylaceta- mide (14.5 mg, 0.0475
mmoles) reacted with 2-methoxy-5-nitrophenylisothioc- yanate (12.6
mg, 0.06 mmoles) in dichloromethane (1 ml) at 60.degree. C.
overnight.
[0461] E38.2
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-bromophenyl)-2-p-
henyl acetamide 169
[0462]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(4-bromophenyl)-2-phenyl
acetamide (19.7 mg, 80.5%); from
2-Amino-N-(4-bromophenyl)-2-phenylacetam- ide (15 mg, 0.049 mmoles)
reacted with 2-methoxy-5-nitrophenylisocyanate (15 mg, 0.077
mmoles) in dichloromethane (0.8 ml) at 60.degree. C. overnight.
[0463] Experiment 39:
[0464] C39*
R-tert-butyl[1-(4-methylphenylcarbamoyl)-1-cyclohexylmethyl]-c-
arbamate 170
[0465]
R-tert-butyl[1-(4-methylphenylcarbamoyl)-1-cyclohexylmethyl]-carbam-
ate (96.9 mg) was isolated as a white solid from
N-tert-butoxycarbonyl D-cyclohexyl glycine (250 mg, 1.1658 mmol),
N-methylmorpholine (0.140 ml, 1.2823 mmol), isobutylchloroformate
(0.166 ml, 1.2823 mmol), p-toluidine (0.149 mg, 1.398 mmol), and
N-methylmorpholine (0.152 ml, 1.398 mmol).
[0466] D39* R-1-Amino-N-(4-methylphenyl)cyclohexane carboxamide
171
[0467] R-1 -Amino-N-(4-methylphenyl)cyclohexane carboxamide (71.1
mg), was isolated as a white solid from,
R-tert-butyl[1-(4-methylphenylcarbamoyl)--
1-cyclohexylmethyl]-carbamate (96.0 mg) stirred with formic acid (2
ml) 50.degree. C. for 2 hours.
[0468] E39*
R-[1-(2-methoxy-4-nitrophenyl)-thiouriedo]-N-(4-methylphenyl)--
cyclohexane carboxamide 172
[0469]
R-[1-(2-methoxy-4-nitrophenyl)-thiouriedo]-N-(4-methylphenyl)-cyclo-
hexane carboxamide (22.9 mg) was isolated as a white solid from
R-1-Amino-N-(4-methylphenyl)cyclohexane carboxamide (35 mg, 0.144
mmol) and 2-methoxy-5-nitrophenylisothiocyanate (39.35 mg, 0.1873
mmol).
[0470] Experiment 40:
[0471] C40 Tert-butyl-[1-(2-cyclohexyl carbamoyl)
-1-(3,4-dimethylphenyl)] carbamate 173
[0472] Tert-butyl-[1-(2-cyclohexyl
carbamoyl)-1-(3,4-dimethylphenyl)] carbamate (265.3 mg) was
isolated as a white solid from the corresponding non-natural amino
acid (300 mg, 1.233 mmol) and N-methylmorpholine (0.15 ml, 1.356
mmol), Isobutylchloroformate (0.175 ml, 1.356 mmol),
3,4-dimethylaniline (179 mg, 1.479 mmol), and N-methylmorpholine
(0.16 ml, 1.479 mmol).
[0473] D40 2-Amino-N-(3,4-dimethylphenyl)-2-cyclohexyl carboxamide
174
[0474] 2-Amino-N-(3,4-dimethylphenyl)-2-cyclohexyl carboxamide was
isolated as a white solid from Tert-butyl-[1-(2-cyclohexyl
carbamoyl)-1-(3,4-dimethylphenyl)] carbamate stirred with formic
acid (3 ml) at 50.degree. C. for 2 hours.
[0475] E40
[1-(2-methoxy-5-nitrophenyl)-thioureido]-N-(3,4-dimethylphenyl)-
]-cyclohexane carboxamide 175
[0476] [1-(2-methoxy-5-nitrophenyl)-thioureido
N-(3,4-dimethylphenyl)]-cyc- lohexane carboxamide (110 mg) was
isolated from 2-Amino-N-(3,4-dimethylphe- nyl)-2-cyclohexyl
carboxamide (50 mg 0.2029 mmol) and
2-methoxy-5-nitrophenylisothiocyanate (55.4 mg, 0.2637 mmol).
[0477] Experiment 41
[0478] C41
tert-butyl[1-(3,4-dimethylphenylcarbamoyl)-1-(3-thienyl)-methyl-
]-carbamate 176
[0479]
tert-butyl[1-(3,4-dimethylphenylcarbamoyl)-1-(3-thienyl)-methyl]-ca-
rbamate (Crude product used in next reaction); from
[(tert-butoxycarbonyl)amino](thienyl)acetic acid (300 mg, 1.165
mmoles) reacted with isobutyl chloroformate (166 .mu.l, 1.282
mmoles) and N-methylmorpholine(0.141 ml, 1.282
mmoles)-2-methyl-4-chloroaniline (169.1 mg, 1.19 mmol) and
N-methylmorpholine (0.154 mL, 1.398 mmol).
[0480] D40 2-Amino-N-(3,4-dimethylphenyl)-2-thienylacetamide
177
[0481] 2-Amino-N-(3,4-dimethylphenyl)-2-(3-thienyl)-acetamide (96
mg); from
tert-butyl[1-(3,4-dimethylphenylcarbamoyl)-1-(3-thienyl)methyl]-carb-
amate (Crude product from previous reaction)) reacted with formic
acid (3 ml) at 60.degree. C. for 0.5 hour.
[0482] E41.1
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3.5-dimethylphenyl-
)-2-(3-thienyl)-acetamide 178
[0483]
2-[3-(2-methoxy-5-nitro-phenyl)-ureido]-N-(3,5-dimethylphenyl)-2-(3-
-thienyl)-acetamide (73.54 mg, 98%) was isolated as an off white
solid from 2-Amino-N-(3,4-dimethylphenyl)-2-(3-thienyl)-acetamide
(45 mg, 0.165 mmol) and 2-methoxy-5-nitrophenylisocyanate (41.7 mg,
0.2147 mmol).
[0484] E41.2
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylph-
enyl)-2-(3-thienyl) acetamide 179
[0485]
2-[3-(2-methoxy-5-nitro-phenyl)-thioureido]-N-(3,5-dimethylphenyl)--
2-(-3-thienyl)-acetamide (71.95 mg, 92%) was isolated as a pale
yellow solid from
2-Amino-N-(3,4-dimethylphenyl)-2-(3-thienyl)-acetamide (45 mg,
0.165 mmol) and 2-methoxy-5-nitrophenylisothiocyanate (45.13 mg,
0.2147 mmol).
[0486] Experiment 42
[0487] C42 (+/-)-Boc-amino-3-thienyl-glycine indan-3-ylamide
180
[0488] Isobutyl chloroformate (0.7 mL) was added to
(+/-)-Boc-amino-3-thienyl-glycine (1.505 g, 5.85 mmol) and
N-methylmorpholine (0.7 mL) in THF (15 mL) and the reaction mixture
was stirred at -78.degree. C. for 1 h. A mixture of 3-aminoindan
(950 mg, 7.13 mmol) and N-methylmorpholine (0.7 mL) in THF (7 mL)
was added and the resulting mixture was stirred for 2 h, slowly
warming to RT. The mixture was partitioned between dichloromethane
(200 mL) and water (50 mL). The organic layer was washed
sequentially with water (50 mL), HCl (1 M, 50 mL), and brine (50
mL) and dried over sodium sulfate. Filtration through a small plug
of silica gel followed by evaporation to remove the solvent yielded
a solid, which was triturated with hexane to provide a product
(1.82 g, 84%) sufficiently pure for the next step.
[0489] D42 (+/-)-3-thienyl-glycine indan-3-ylamide 181
[0490] A mixture of (+/-)-Boc-amino-3-thienyl-glycine
indan-3-ylamide (1.82 g, 4.89 mmol) and formic acid (96%, 20 mL)
under Ar(g) washeated at 60.degree. C. for 35 min. After cooling to
RT, the formic acid was removed in vacuo. The crude product was
taken up in dichloromethane (200 mL) and washed sequentially with
NaOH (1 M, 100 mL) and brine (100 mL), dried over sodium sulfate,
and the solvent was removed in vacuo. The oily residue was
solidified by pumping, and then triturated using hexane to provide
a product (1.19 g, 89%) sufficiently pure for the next step.
[0491] E42.1
N-(indan-5-yl)-2-[-3-(2-methoxy-5-nitrophenyl)-uerido-2-(3-th-
ienyl-acetamide 182
[0492] From the amine (351.7 mg, 1.29 mmol) and
2-methoxy-5-nitrophenyliso- cyanate (318 mg, 1.64 mmol) in
dichloromethane (10 mL) at 60.degree. C. for 3h. Collected
precipitate and rinsed using dichloromethane (5.times.5 mL).
Product was a yellow solid (605.6 mg, 100% yield, %, HRMS-FAB.sup.+
for C.sub.23H.sub.22N.sub.4O.sub.5S: calculated MH.sup.+:483.13270;
found:483.11331).
[0493] E42.2
N-(indan-5-yl)-2-[-3-(2-methoxy-5-nitrophenyl)-thiouerido-2-(-
3-thienyl-acetamide 183
[0494] From the amine (351.0 mg, 1.29 mmol) and
2-methoxy-5-nitrophenyliso- thiocyanate (345 mg, 1.64 mmol) in
dichloromethane (10 mL) at 60.degree. C. for 3.5 h. Collected
precipitate formed by cooling in ice and rinsed using
dichloromethane (5.times.5 mL). Product was an off-white solid
(577.5 mg, 93% yield, %, HRMS-FAB.sup.+ for
C.sub.23H.sub.22N.sub.4O.sub.- 4S.sub.2: calculated
MH.sup.+:467.13892; found:467.13985).
[0495] Experiment 43
[0496] Assay of Transport via GlyT-1
[0497] This example illustrates a method for the measurement of
glycine uptake by transfected cultured cells.
[0498] Cells stably transfected with GlyT-1 C (see Kim, et al.,
Molecular Pharmacology, 45, 1994:608-617) were washed twice with
HEPES buffered saline (HBS). The cells were then incubated for 10
minutes at 37.degree. C. with either (a) no potential competitor,
(b) 10 mM non-radioactive glycine or (c) a concentration of a
candidate drug. A range of concentrations of the candidate drug was
used to generate data for calculating the concentration resulting
in 50% of the effect (e.g., the IC.sub.50s, which are the
concentrations of drug inhibiting glycine uptake by 50%). A
solution was then added containing [.sup.3H]glycine at a final
concentration of 50 nM (17.5 Ci/mmol). The cells were then
incubated with gentle shaking for another 30 minutes at 37.degree.
C., after which the reaction mixture was aspirated and washed three
times with ice-cold HBS. The cells were lysed with scintillant and
allowed to equilibrate. The radioactivity in the cells was
determined using a scintillation counter. Data was compared between
the same cells contacted or not contacted by a candidate agent,
depending on the assay being conducted.
[0499] The compounds of the present invention were active as GlyT-1
inhibitors. The following table provides examples of the glycine
uptake IC50 values for representative compounds of the
invention.
1 Experiment Number GlyT1 uptake IC50 (nM) E42.2 131.4488 E32.2
333.9854 E32.5 25.9085 E33.1* 96.0385 E42.1 113.714 E29.1* 71.9265
E4.1 67.3383 E31.2 202.0483
Example 43
[0500] Assay of Binding to NMDA Receptors-associated Glycine
Binding Site
[0501] This example illustrates a method used to measure the
interaction of compounds to the glycine site on the NMDA receptor.
In this assay a known NMDA glycine site binding agent,
(tritiated-MDL 105519, available from Amersham), is used to bind to
rat hippocampal tissue. The test compound is then introduced and
allowed to displace the hot ligand. Binding of the test compound
will displace the hot ligand and result in reduced radioactivity,
which can be quantified. Compounds are generally tested at two
concentrations if inhibition is observed the compounds are retested
at several concentrations to generate a dose response curve from
which an IC50 may be determined.
[0502] The test compounds are prepared for the assay by diluting
with 50 mM Tris Acetate buffer. Rat hippocampal membrane aliquots
used in the assay are washed twice with cold 10 mM Tris Acetate
buffer and subjected to ultracentrifugation at 20,000 rpm for 15
minutes, and rehomogenization between washes. The final pellets are
then resuspended in 50 mM Tris Acetate buffer to provide the
membranes at a concentration appropriate to the assay. Non-specific
binding is defined in the presence of 1 mM glycine. Total binding
is defined by the presence of Tris acetate buffer only.
[0503] The reaction mixture is prepared by combining 75 .mu.g of
homogenized hippocampal membrane preparation with [3H]-MDL 105519
to a final concentration of 5 nM and glycine or test compound as a
solution in Tris Acetate Buffer. The reaction is shaken while
incubating at room temp for 30 minutes. The plates are then
harvested onto GFC filters using a 48 w Brandell Harvestor. The GFC
filters are pre-treated for at least 30 minutes with a solution of
0.5% BSA made in distilled water to reduce non-specific binding of
the hot ligand to the filter. The plate wells are washed with 4-5
volumes of cold 50 mM Tris Acetate buffer. The filters are then
transferred to scintillation vials and 2 mls of scintillant is
added to each vial. The vials are allowed to sit overnight before
being counted in a Beckman .beta.-counter. The data is analyzed
using Prism software.
[0504] The compounds of the present invention show no significant
binding to the NMDA receptor-associated glycine binding site.
Example 44
[0505] Glycine Receptor Binding Assay
[0506] This example illustrates an assay used to measure cross
reactivity of the compounds with the Glycine receptor. In this
assay the known glycine receptor binding agent, [3H]-Strychnine is
used to bind to rat spinal cord tissue. The test compound is then
introduced and allowed to displace the hot ligand. Binding of the
test compound will displace the hot ligand and result in reduced
radioactivity, which can be quantified. Compounds are generally
tested at two concentrations, if inhibition is observed the
compounds are retested at several concentrations to generate a dose
response curve from which an IC50 may be determined.
[0507] The test compounds are prepared for the assay by diluting in
potassium phosphate buffer. The aliquots of rat spinal cord
membrane used in the assay are washed with two portions of cold
Phosphate buffer followed by microcentrifugation at 4.degree. C.,
at 14,000 rpm between washings. The final pellets are then
resuspended in a volume of phosphate buffer to provide
concentrations appropriate to the assay conditions. The
non-specific and total binding are defined by 10 mM final
concentration of glycine and phosphate buffer only,
respectively.
[0508] The reaction mixture is prepared by combining 150 .mu.g of
the rat spinal cord membrane with [3H]-strychnine to a final
concentration of 7 nM and glycine or test compound. The reaction
mixture is incubated for two hours while shaking on ice. The plates
are then harvested onto GFC filters using a 48 w Brandall
Harvestor. The GFC filter is pre-treated for at least 30 minutes
with a solution of 0.5% BSA made is distilled water to reduce
non-specific binding. The plate wells are washed with 4-5 volumes
of cold phosphate buffer. The filters are then transferred to
scintillation vials and 2 mls of scintillant is added to each vial.
The vials are allowed to sit overnight before being counted in a
Beckman .beta.-counter. The data is analyzed using Prism
software.
[0509] The compounds of the present invention show no significant
binding to the glycine receptor.
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